The Autism PolyPill 5 years on from December 2012

2^nd WOW!

Still autistic, but less so, and no longer cognitively challenged.

It is exactly five years since Monty, now aged 14 started his Polypill therapy. At first it was just bumetanide, but shortly thereafter NAC and atorvastatin were added, more followed later.  All without any side effects.

I received Monty’s end of term school report just before Christmas and it bears little resemblance to what he received back in 2012. Now it does not look like the report of someone who is cognitively challenged. Almost all the grades are As; these are his best ever results and unlike 5 years ago, these are the same tests as taken by his NT peers, not an easy version. 

At the beginning of this first year in high school, there was a view that Monty should not be there, that he would fail to cope and later have to leave; he has proved otherwise.  None of this was malicious; it was just that the head of the high school used to teach in the junior school and has known Monty since he was four years old. Back then, and until he was nine years old, he was seriously challenged, academically. The post-Polypill Monty came as a big surprise, he is still autistic, but now academically functional.  He is now never disruptive and behaves like an attentive model student, just one that does not talk much.

Monty’s assistant recently asked me why, since some doctors do read this blog and apply it, don’t more doctors now treat their kids with autism? She mentioned a top local neurosurgeon who has twins with severe autism; why isn’t he treating his own kids? If you can do it, why can’t he? My answer was that a neurosurgeon is not a neuroscientist.   His job is quite primitive; he drills holes in people’s skulls and pokes around for visible defects in the brain. Treating autism is about tweaking tiny things like ion channels that you cannot even see. Being a neurosurgeon does not really help much, unless you read the neuroscience literature, which he likely does not.  

Wow Moments

I do like “Wow moments”. They do not come very often, the last one was four years ago when I first saw a little yellow pill (Verapamil) make an extended episode of self-injury, melt away in front of my eyes. That was like winning the Lottery and this therapy continues to have the same effect.

A “Wow moment” occurred in late December when I opened the end of term report, of Monty’s NT big brother, who attends the same school.  Monty’s grades are better. Yes, Monty is in year 7 and big brother is in year 13, his final year of school. You should not compare one sibling with another sibling, but nobody would have dreamt that a boy with classic autism would ever outshine his intelligent NT brother academically, under any circumstances. I think that deserves a “Wow”. Even big brother was impressed by little brother.

Nowadays an autism diagnosis usually is not associated with MR/ID; it is much more likely to be better described as a variant of Asperger’s. If you have Asperger’s there is no reason you should not aim for College/University. Unfortunately that is not Monty’s case, he has strictly defined autism (SDA), meaning more severe biological dysfunctions and his school reports from 5 years ago reflected that. He could not function academically; school was more for “socialization”.  People with SDA usually do not make it past the basics of school academically.  Where we live, autism = SDA and severe autism means something extremely challenging, so I find it very strange to read comments on the internet written by people claiming to have severe autism themselves.

One medical researcher recently asked me how effective is sodium benzoate (NaB) proving as a cognitive enhancer. All I could say was the current level of academic performance is shocking everyone. We had teachers thinking the assistants were boosting his test performance, so we all agreed to be super careful not to give help during tests. So now they are 100% his work, before I think it was 90% his work with some “hinting”.  I cannot say with certainty whether NaB helps or not. I stopped for a week over Christmas, and I concluded that there may well be a difference.

The extreme case of “hinting” is so-called facilitated communication, when the assistant ends up doing 90% of the work. The result is an illusion of what you would like to think the child is capable of, rather than reality. We do not need any of that.

There are also prompting methods like RPM, but at the end of the day what matters is what the child can eventually achieve entirely unaided. It does not matter if they type their work, or handwrite it.

Is the OAT3 inhibitor helping? For the last few weeks I have used coffee flavanols to boost the pharmacodynamics of bumetanide (by delaying its excretion). 

There are still plenty of ideas I have not yet implemented (RORα, PDE4 etc.) but the current PolyPill has delivered results far beyond my expectations. I do not think it is realistic to go from strictly defined autism (SDA) to entirely NT. The target I mentioned long ago was to go from SDA to something like Asperger’s. Monty is never going to be quite like his older brother, but after 5 years he now evidently has a typical level of IQ, and most importantly he can apply it at school and in daily life.

This Christmas Monty made his way through the self-scanning passport control at the airport and when randomly selected for the whole body scanning machine, he coped without incident.  Air travel is now a highlight of a trip and the more turbulence the better.

Now to the next five years.

The open question is whether Monty can obtain formal educational qualifications. In the English system there are externally assessed exams at age 16 (year 11) and at age 18 (year 13). Monty’s class group are two years his junior, so he will be 18 at the year 11 assessment. Years ago our piano teacher, who only teaches people with special needs, was pretty blunt about the fact that none of her kids leave school with formal qualifications, except sometimes in music. 

The situation varies greatly depending on where you live.  In the US things are very different and if you have an IEP (Individualized Education Program) and attend high school, you automatically seem to “graduate” high school with some kind of diploma. Many people with an IEP in the US do not have severe learning disabilities and they graduate with the standard diploma.

Monty has never had an IEP because he does not go to a school that offers them. In effect he has had a very customized education program for more than a decade, just it was run from home.

Childhood Disintegrative Disorder (CDD) – Not a Useful Diagnosis?

Today’s post is about CDD (Childhood Disintegrative Disorder) also known as Heller’s Syndrome, which sounds rather nicer. It was first identified in 1908 by an Austrian, Theodore Heller. Later on came Hans Asperger, another Austrian and Leo Kanner who was born in what was the Austro-Hungarian Empire.

Why were Austrians so interested in Autism?

I started this post expecting that I would naturally be a supporter of the continued use of CDD as a diagnosis, I do firmly support calling an Aspie an Aspie after all. 

CDD is a diagnosis used for late onset severe regressive autism, which has fast onset, making it scary for all concerned.

Unlike many syndromes, Rett for example, Heller’s syndrome is not a defined genetic condition, it is just another observational diagnosis. This probably explains why it has been folded into the ASD diagnosis in the current DSM5, which sadly was also the case with Asperger’s.

Since it is not really a syndrome I will call it by its other name CDD (Childhood Disintegrative Disorder). I have not previously given much mention to CDD in my blog because I had assumed it was much worse than “regular” severe autism and that the disorder was well defined, so that it would be a clear case of CDD or autism.  It turns out this was a mistake. 

Back in 1994

In 1994 when Yale researcher, Fred Volkmar, was writing about CDD and severe autism he noted

More boys than girls appear to be affected. Childhood disintegrative disorder is perhaps 10 times less common than more strictly defined autism and is estimated to occur in between 1-2 children per 100,000. 

Field trial for autistic disorder in DSM-IV

He was thinking strictly defined autism (SDA) was present in 0.015% of the population (15 children per 100,000), whereas I think today it is 0.3% (300 children per 100,000). I have got by zeroes in the right place. That is a massive twenty-fold increase in severe autism in 20 years, something that is never seriously investigated because DSM5 autism now includes 1% (1,000 children per 100,000) who have mild autism (mainly Asperger’s), so no statistics are directly comparable. 

Present Day

In today’s post we will see that CDD is just another broad umbrella term for a large number of different, often genetic, disorders. The case of CDD presented by a Yale researcher below appears to show a young lady less severely affected than many people with a diagnosis of severe autism. 

The most terrifying childhood condition you’ve never heard of

Well in case of Gina in the above article, it looks no worse than “regular” severe autism, certainly not terrifying. She rides a bicycle and helps around the home.

The Yale researcher in the above article is rather indignant that his disorder has “disappeared” into autism in DSM5 and so now he struggles to get funding.  What is telling is his comment that if you had a CDD diagnosis, clinicians would then naturally look for its biological origin, but now with a diagnosis of autism with ID (Intellectual Disability), no clinician will investigate further. Why is that??

The distinction has clinical implications. With a CDD diagnosis, the initial push is to hunt for a reversible cause. If the patient is diagnosed with autism and intellectual disability instead, that hunt never happens. "This means we may be missing a whole world of possible treatments for kids on the low-functioning end," says Westphal. 

Now this raises a question of why people with CDD are more worthwhile investigating, than anyone else. Surely all cases of severe autism should be investigated? There are no more wonder cures for CDD than there are for any other autism. As we have seen previously, there are numerous rare inborn errors of the metabolism that cause autism/ID that are treatable. 

Westphal wrongly assumes that there are no possible therapies for severe idiopathic autism. 

CDD as a sub-type of regressive autism

It would seem best to consider CDD for what it is, late onset regressive autism, with or without a “prodrome”, which is a distressing period of great anxiety lasting a month or two as the regression from normal to severe autism takes place.

In the young lady profiled in the above article, there was no prodrome and her regression took place at 3 years old and left her in a condition better than some I know with an autism diagnosis.

So here I actually agree with DSM5 that she would be better off with an autism + ID diagnosis; she should then have been taken to Johns Hopkins to see Dr Kelley, to check for mitochondrial disease. She looks no different to one of his cases of severe autism secondary to mitochondrial disease (AMD).

It looks like genuinely late regression, say 5 to 10 years old, points to some rare disorders like leukodystrophy, which is itself a family of genetic myelination disorders. These can be late onset and are degenerative.

Very likely within what has been diagnosed as CDD are hundreds of rare disorders, some degenerative but most not. It is the degenerative potential that makes CDD scary, but most people do not have this.

Some of these non-degenerative disorders will overlap with people diagnosed with severe autism, which itself likely includes many hundreds of rare biological disorders.

It certainly is important to get as precise diagnosis/description of each type of autism as possible.

So why not keep CDD along with Asperger’s as sub-categories of autism? All these rather vague observational diagnosis carry risks. You can have mitochondrial disease at age 5 that causes a regression to severe autism, I think the Yale team might well (mis)diagnose that as CDD, which is much more of an arbitrary diagnosis than I had realized.

An important issue is whether the disfunction is degenerative or not. It turns out that in a small number of CDD cases, the disintegration continues to an early death, but in most cases the condition becomes stable and in a small number of cases there is partial recovery, as with Dr Kelley’s AMD. This tells us that the observational diagnosis is pretty pointless. As always, what matters is a biological diagnosis.

The CDD researchers think some people with severe autism have CDD. I think people with CDD either have a rare genetic dysfunction, which may or may not be degenerative, they have mitochondrial disease, or it is “just” another case of idiopathic autism (the “I don’t know” category). So I do not really see the point of the CDD diagnosis.

The diagnosis should be ASD, its severity, speech delay or not, cognitive level, nature and time of onset, and then possible biological origin based on genetic testing. 

Conclusion

I think people diagnosed with CDD, who have no identifiable genetic disorder, really need to get tested for mitochondrial disease.

I wish some more intelligent people were in charge of autism research and collecting and interpreting data on prevalence. Is it possible that the prevalence of Strictly Defined Autism (SDA) was just 0.015% in 1994, versus 0.3% today? That means going from very rare to just rare in two decades. Maybe clinicians back then diagnosed a much larger group simply with MR/ID, that today would get diagnosed with autism + MR/ID. Pre Dr Wakefield and the MMR vaccine scandal, autism was rarely spoken about, even among doctors; today it has become quite a fashionable diagnosis. That is the best explanation I can think of; we do know that the diagnosis of MR/ID has fallen substantially in the last decades. 

Turner Syndrome, Estradiol and Autism-lessons from the X Chromosome

This post is best read if you have reviewed the earlier ones regarding the estradiol/testosterone disturbances in autism and how they govern the RORα “switch” that then triggers a torrent of other dysfunctions. So the hormonal disturbance, if present, is a key point at which to make a potent intervention. 

The Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis in Autism 

Beauty is in the eye of the beholder

In the mass media it is now popular to dismiss the fact that autism is far more prevalent on boys than girls. In the scientific literature, fortunately, they stick to the facts and much is written about the sex differences in autism.

As we have seen in earlier posts, females have some natural defences against autism. They have two X chromosomes and of course they have those all-important neuroprotective female hormones (estrogen/estradiol, progesterone etc.). In effect, the more female you are, the more protection you have against idiopathic autism and any X-chromosome linked single gene autism. So a girl with Fragile-X syndrome is likely to be far less affected than her brother with same condition.
Recall that we all have 23 pairs of chromosomes and that the 23^rd set contains two Xs in girls and in boys one X and one Y. The girls’ “spare” X chromosome is also what gives them their feminine features.  

It is interesting to look what happens to females who lack part of their second set of X- chromosomes. This diagnosis is called Turner Syndrome. As you might have guessed people with Turner Syndrome have much lower levels of female hormones and a higher incidence of autism, although some people find this controversial. The autism-like characteristics of TS include:-

·      Impairments in social functioning

·      Impairments in face and emotion processing

·      Spatial executive deficits

·      Poor social coping skills and increased immaturity

·      Hyperactivity and impulsivity

Turner syndrome occurs in 50 per 100,000 live-born females. Autism occurs about ten times for frequently, so about 500 per 100,000 live-born females.  Turner syndrome provides the extreme case of what happens when females have too little estrogen/estradiol.

I think you will find a large group of females with idiopathic autism (no identified genetic defects) have/had low levels of estradiol. I think this is the reason that facial recognition studies show that some females with idiopathic autism look different, (as do many boys, of course). We already know that most single gene types of autism produce tell-tale signs, often on the face (big ears, wide face, big/small head etc).

I am not suggesting that there is anything wrong with looking different; rather it may be a useful diagnostic tool and not an expensive or invasive one. Physical variation has long been used to identify genetic syndromes, before genetic testing became widely available.

Physical variation inside your head

We saw in an earlier post that MRI scans of the autistic brains actually do often show subtle differences, particularly when you use software to read them, rather than the naked eye. Traditionally doctors say that MRIs are “normal” in autism and cannot be used to diagnose it. Yet in a recent studies machine reading of MRIs was able to identify 70%-96% of autism cases.  Some of these are scans taken before birth.

This is interesting, because ultimately you might bypass the current very slow and subjective observational diagnosis process.

Brain imaging studies seek signs of autism before birth

Infant MRIs show autism linked to increased cerebrospinal fluid

MRIs show a brain anomaly in nearly 70 percent of babies at high risk of developing the condition who go on to be diagnosed, laying the groundwork for a predictive aid for pediatricians and the search for a potential treatment

Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age

Predicting the future with brain imaging

In a new study, Emerson et al. show that brain function in infancy can be used to accurately predict which high-risk infants will later receive an autism diagnosis. Using machine learning techniques that identify patterns in the brain’s functional connections, Emerson and colleagues were able to predict with greater than 96% accuracy whether a 6-month-old infant would develop autism at 24 months of age. These findings must be replicated, but they represent an important step toward the early identification of individuals with autism before its characteristic symptoms develop.

A Breakthrough AI Can Now Predict Which Babies Will Develop Autism

MRI scanners are very widely used, but you do have to keep very still inside when they are in operation. The even harder part is the reading of the data. It is clear that some standardized machine reading (A/I artificial intelligence) process is required to notice every possible variation. You could have a centralized location where you just submit your MRI data, the center gets to keep the data and learn from it; and you get their insight as to what differences there might be.

Facial Differences vs MRI Brain Differences

I like to keep things simple and under my control.  In the short term we have to settle for facial differences, since any well-managed MRI process will be decades away.

Hormonal Variation in Autism

Hormonal differences were one of the key areas I identified years ago in this blog. Big/small heads result from disturbances in pro-growth signalling pathways. We should expect variations in bone-age, early/late onset of puberty and indeed big variations in height and weight.

In Turner Syndrome, the girls tend to be very short and they are often treated with growth hormones, as well as female/feminizing hormones.  

Great caution has to be taken when treating children with any hormones. When children are treated, it is for serious reasons like not achieving puberty, or having a serious growth delay (being very short).

Hormone Therapy During Pregnancy

In some countries hormones are given during pregnancy although I think this would be seen as odd/risky in some advanced countries.

We have already seen that couples who have difficulty producing a child often have a family history that includes autism. It was proposed by one serious fertility expert that what helps prevent miscarriage also helps prevent autism. This did sound odd when I first read about, but when you look in more depth there is a basis for this idea.

That expert has these two websites:-

http://www.preventautism.com/

http://www.preventmiscarriage.com/

Progesterone supplements have been recommended for more than 50 years for women struggling with infertility, but research now shows they can also help prevent miscarriage.

Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss

Tamoxifen, an estrogen receptor (ER) antagonist, is also used to treat infertility.

Estradiol is sometimes prescribed during pregnancy.

Testosterone is produced naturally during pregnancy.

All this is clearly beyond the scope of this blog, but perhaps altered female/male hormones during pregnancy might be a biomarker of some future autism and female hormones might be a protective therapy in the subgroup of pregnant mothers with low levels of these hormones and/or high levels of testosterone. Recall that human trials in the hospital ER have shown certain substances are highly neuroprotective (progesterone, atorvastatin etc) and when administered immediately after a traumatic brain injury markedly improve the outcome.                                         

Hormone Therapy for Autism

Hormone therapy in people with autism would be controversial, but we saw in an earlier post that via RORα the balance between testosterone and estradiol affects numerous biological relevant to autism.

Many pictures of girls/women with autism, that you can view online, suggest reduced levels of estradiol. Faces look more boy-like. Many males with autism are reported to have physical features of high testosterone and low estradiol. 

One example of many:-

https://www.npr.org/2017/11/28/566788182/navigating-life-on-campus-when-youre-on-the-autism-spectrum

Both faces in the above article show clear indications of autism. Since both young people do have autism, this should not surprise anyone.

My own conclusion is that if you have autism or Asperger’s, a little extra estradiol could therapeutic, particularly if you have physical features that reinforce this.

There are of course many males and females with autism who are physically indistinguishable from the rest of the world. The point of this post is to highlight that visible differences may help to define the sub-type of autism and indicate possibly effective therapies, that exist today.

Obesity and Estradiol

In an earlier post on estradiol, I pointed out that in males estradiol is made in your adipose (fat) tissue. In the US many people with autism are overweight, in part due to side effects from their likely un-needed psychiatric medications; this has the hidden benefit of increasing their estradiol levels, feminizing their behavior slightly and shifting RORalpha in the right direction.

This also means that losing weight should be helpful to obese females with estrogen receptor positive breast cancer.  Research does support this.

Asperger’s and too much Estradiol?

We saw in earlier posts that much autism is associated with reduced expression of estrogen receptor beta and low aromatase, so high testosterone and low estradiol.

We have seen on many occasions that when one extreme exists in autism, so usually does the other; so many big heads, but also some tiny ones, NMDAR hypofunction, but also hyperfunction.

There was a lot of talk a while back in the media about children undergoing therapy to change their gender, and it was highlighted that Asperger’s was much over-represented in this group. One expert got into trouble for suggesting that their autism was causing them to obsess about their identity and so mistakenly convince a boy that he would rather be a girl.  It seems that these days some clinicians are then all too willing to provide drug therapy and then operate on them, to make them female.  I do wonder if perhaps some of these boys with Asperger’s might have the other extreme of aromatise. That would give them too little testosterone and too much Estradiol.

I think measuring these hormones is quite a good idea, as I keep repeating, they go on to affect the critical “switch”  RORα, which then impacts a large number of biological processes implicated in autism.  In other words you can try to normalize a wide range of important autism variables, just be tweaking RORα, via estradiol/testosterone.

A boy with high testosterone, and so low estradiol, will likely exhibit physical signs of this, just like the girl with low estradiol. These are just pieces of the puzzle, in plain view, that can be used to understand each specific case of autism. And no machine reading of an MRI is required.

For those left wanting more:

A very thorough paper on Turner Syndrome:-

Turner Syndrome

Turner syndrome (TS) is a neurogenetic disorder characterized by partial or complete monosomy-X. TS is associated with certain physical and medical features including estrogen deficiency, short stature and increased risk for several diseases with cardiac conditions being among the most serious. Girls with TS are typically treated with growth hormone and estrogen replacement therapies to address short stature and estrogen deficiency. The cognitive-behavioral phenotype associated with TS includes strengths in verbal domains with impairments in visual-spatial, executive function and emotion processing. Genetic analyses have identified the short stature homeobox (SHOX) gene as being a candidate gene for short stature and other skeletal abnormalities associated with TS but currently the gene or genes associated with cognitive impairments remain unknown. However, significant progress has been made in describing neurodevelopmental and neurobiologic factors underlying these impairments and potential interventions are on the horizon

Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay.

We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, 

Facial features provide clue to autism severity

  

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

Today we have a complex dysfunction, but we have a plausible understanding of the detailed biological underpinnings and several therapeutic options. It is relevant to people with autism who have impaired sensory gating (they find noises like a clock ticking annoying), and perhaps those who struggle with complex thought. It is very likely to be disturbed in some people with ADHD and many with schizophrenia.

Trouble in the Pre-Frontal Cortex

For a recap on sensory gating, here is an earlier post:-

Sensory Gating in Autism, Particularly Asperger's

Today’s dysfunction relates to HCN channels located on those tiny dendritic spines in a part of the brain called the pre-frontal cortex. These are a type of voltage gated potassium channel found in your brain and heart, there are 4 types, it looks to me that HCN2 is the key one today.

The pre-frontal cortex (PFC) is seen as the part of the brain most affected by mental illness (schizophrenia, bipolar, ADHD etc.), although medicine’s current understanding looks rather medieval to me.

These HCN channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network (created by numerous interacting neurons) is effectively disconnected.

By keeping these channels closed, it is thought that you can improve working memory and reducing distractibility. Now you might think distractibility is an odd word, and it is not a word I expected to encounter, what it really means is impaired sensory gating. This is a core feature of Asperger’s, ADHD and schizophrenia.

One of the key risk genes for schizophrenia, DISC1, also affects HCN channels and this may account for some of the cognitive deficit found in schizophrenia. High level thinking is particularly affected.  It is thought that loss of DISC1 function in the PFC would likely prevent proper PDE4 function, leading to a dysregulated build-up of cAMP in dendritic spines resulting in excessive opening of HCN channels

Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction

I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way.

Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic  receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.

Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

This would explain why stress makes people’s sensory gating problems get worse. So someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. In Monty, aged 14 with ASD, the only time he exhibits significantly impaired sensory gating, is when he has stopped all his Polypill therapies for several days. I think stress/anxiety is what has changed and this opens those HCN channels. Then even the sound of someone eating food next to him makes him angry.

Excessive opening of HCN channels might underlie many lapses in higher cognitive function.

While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.

The University of Maastricht holds patents on the use of Roflumilast, a PDE4 inhibitor, to improve cognition; most interestingly, this takes effect at one fifth of the COPD dosage, for which it is an approved drug. At high doses PDE4 inhibitors have annoying side effects, but at low doses they tend to be trouble-free.

One effect of a PDE4 inhibitor is that it reduces cAMP. So a PDE4 inhibitor acts indirectly like an HCN blocker.

Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.

So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today. This is something that should indeed be investigated across different types of cognitive dysfunction.

There are numerous dysfunctions that can impair cognition and they can occur in different diagnosis. For example impaired autophagy is a key feature of Huntington’s, impaired remyelination defines multiple sclerosis, low levels of nerve growth factor are a key feature of Rett syndrome. Less severe dysfunctions of these processes occur in entirely different conditions.

It is thought that people with Alzheimer’s might benefit from PDE4 inhibition. If it was me, I would try it in all types of dementia or cognitive loss of any kind.

PDE4 Inhibitors

There have been many mentions of PDE4 inhibitors elsewhere in this blog. They are broadly anti-inflammatory and anti-oxidant, but currently only widely used to treat asthma in Japan and COPD in Western countries. COPD is a kind of very severe asthma.

Traditionally a PDE4 inhibitor is thought of as drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). That all sound complicated, just think of it as increasing cAMP.

Now cAMP is a messenger in many biological processes, one of which relates to PKA (Protein Kinase A). In autism we know that PKA, PKB and PKC are often disturbed. These PKs are very important because they have the ability to literally change the function of thousands of proteins in your body. This is similar to how epigenetic tags can switch on or switch off a particular gene. PKs, via a different mechanism we will look at in another post, change the function of proteins, so it is very important that you have the correct level of PKA, PKB and PKC.

We saw in a recent post that the Pitt Hopkins gene TCF4 is regulated by PKA and that under-expression of TCF4 is also a feature of some ID and schizophrenia. So more PKA, please.

The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A 

You can use a PDE4 inhibitor to increase cAMP, which then increases PKA.

Other effects of PDE4 inhibitors

Today’s post is about sensory gating and the effect here of PDE4 inhibitors is via the effect of cAMP on those HCN channels in your tiny dendritic spines.

There are numerous other effects of PDE4 that may also be therapeutic. One interesting effect is that inhibition of PDE4 can mimic calorie restriction by activating AMPK/SIRT1 pathway.

Calorie restriction has just been shown in a large trial to be able to reverse type 2 diabetes, if initiated with a few years of the disease developing.

Humans have evolved based to periods of feast and famine. Periods of fasting may be therapeutic for many modern conditions.

Not surprisingly one side effect of PDE4 inhibitors is weight loss. Many psychiatric drugs cause troubling weight gain.

Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 

Abstract

 

INTRODUCTION:

Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.

METHODS:

The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).

RESULTS:

Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.

CONCLUSION:

The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.

Treating Cognitive Impairment with Roflumilast, Maastricht University

Background Information

Selective phosphodiesterase (PDE) inhibition has been considered as a very promising target for cognition enhancement.

Roflumilast is a PDE4 inhibitor that has been developed by Takeda for Chronic Obstructive Pulmonary Disease (COPD). In recent year, Maastricht University has been collaborating with Takeda to develop Roflumilast for cognitive impairments

In 2015 Takeda sold COPD indication of Roflumilast to AstraZeneca, and ownership of IP for treatment of cognitive impairment returned to Maastricht University.

Compelling clinical results

A single administration of Roflumilast improves episodic memory in mice, and in young and elderly healthy subjects at a non-emetic dose

As shown in the figure, healthy (A) and memory impaired (B) elderly subjects showed better performances in the delayed recall of the Verbal Learning Task after roflumilast

Key Features and Advantages

Opportunities to reposition a clinically-proven safe compound with a well-established pharmacology.

Compelling preclinical and clinical evidences showing that Roflumilast effectively deliver to the brain to produce robust cognitive enhancement.

Pro-cognitive effects at low dose (5 times lower than COPD indication), which allows to circumvent the emetic effects commonly observed with other PDE4 inhibitors

Maastricht University has a strong IP protection extending to at least 2033.

Effect of Roflumilast on cognitive function in schizophrenia

PDE inhibitors in psychiatry--future options for dementia, depression and schizophrenia?

Author information

Abstract

Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.

Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment

The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.

Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."

Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical  norepinephrine or by medications like guanfacine.

 “Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”

Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

The full Yale paper:

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Guanfacine for the Treatment of Cognitive Disorders: A Century of Discoveries at Yale

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette’s Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Nicotine blocks the hyperpolarization-activated current Ih and severely impairs the oscillatory behavior of oriens-lacunosum moleculare interneurons.

Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

Modulation of HCN channels in lateral septum by nicotine

Conclusion

I think many people stand to benefit from the drugs mentioned in today’s post, but for different biological reasons. A person with Pitt Hopkins may benefit from Roflumilast because it will upregulate PKA and then increase expression of their remaining TCF4 gene.

In a person with schizophrenia there are multiple reasons these drugs might help them and it will depend on which genes they have that are misexpressed (TCF4, DISC1 etc.).

In a person with idiopathic Asperger’s and impaired sensory gating it looks like the effect on HCN channels is what is important.

I think low dose Roflumilast has great potential for many. The Japanese drug Ibudilast very likely will provide similar benefits, but at what dosage?

PDE4 inhibitors do have side effects at higher doses in part because there are several different types of PDE4 (PDE4A, PDE4B, PDE4C etc) and different drugs effect different subtypes differently.

Ibudilast is used as a daily drug therapy for asthma in Japan and is being studied as a therapy for Multiple Sclerosis (MS) in the US.

Roflumilast is sold by Astra Zeneca as Daxas/Daliresp but at a high dose of 500mcg to treat flare ups of COPD (Chronic Obstructive Pulmonary Disease) it does cause troubling side effects, but it reduces your chance of dying from COPD.

The cognitive dose used in research is 100mcg. Higher doses had no cognitive/sensory gating benefit.

Further investigation of the ADHD drug Guanfacine should be made, because some of the people who benefit from a PDE4 inhibitor might get a similar effect from Guanfacine. People with Pitt Hopkins would not be in this category. A person with Asperger’s and impaired sensory dating should respond to Guanfacine, a cheap drug.

At the end of the day, choice of therapy will come down to side effects and cost. In the US, Roflumilast is expensive ($330), seven times more expensive than in some other countries; in the UK the price of the same 30 tablets is $50. One pack would be enough for 5 months at the suggested dose.

Trajectories of Intellectual Development in Autism

Tracking IQ over a 3-4 year period, in 4 sub-groups of 2-8 year olds

Today’s post is about trajectories of intellectual development in autism, which I have to come to believe is the most important aspect of autism and certainly helps you understand where your type of autism fits in.

As regular readers may recall average IQ = 100 and the IQ scale fits a bell-curve, so most (68%) people have an IQ within the range 85-115.  2.1% of the general population have an IQ less than 70, which is the cut off for a diagnosis of MR/ID (Intellectual Disability).

There are special tests to measure IQ in non-verbal people and IQ testing is matched to your age; so the older a child gets the more there is expected from them in the test.

I do wonder how you can fairly test the IQ of a 2 year old with severe autism. So I think some testing in very young children may substantially underestimate IQ. 

A study was recently published taking data from the Autism Phenome Project run by UC Davies.

What will my child's future hold? phenotypes of intellectual development in 2-8-year-olds with autism spectrum disorder.

Even though the sample size is only a hundred, what makes it interesting is that it is a longitudinal study, meaning they collect data from the same kids over a period of many years.

Welcome to the Autism Phenome Project

They fitted data from the hundred kids into four groups and then took the average IQs within each group. The kids had IQ measured twice, not at exactly the same ages, but about 4 years apart. (The youngest at T1 was two years old and the oldest at T2 was eight)

I used their data and apply my interpretation. I do not think they made the most of their own data.

So the first group (black) are the Asperger’s kids who were 22% of the sample group.  This group started out at 2-3 years old with IQ just under 100 but in the next 4 years they raised their cognition at an above average rate, so that average IQ rose to 110. Not bad going.   Average IQ in the general population is 100.

Classic autism is the red group at the bottom and as expected their IQ starts out low and gets worse, because they add skills at a lower rate then NT kids, so even though they learn, their measured IQ falls. This group was 26%.  Even though the sample is very small at 100, this is close to my estimate of classic autism (SDA) being about 30% of all autism. In some countries you have to measure IQ to access services. Our behavioral consultant was not a fan, because the parents get upset when IQ goes down over time, so we never measured IQ. The red line is even lower than I had expected.

The green line I called responsive autism, because even though IQ is low it does not fall during the 4 years period where it was measured. This group account for 18% of the total. These children are acquiring new skills at a fair rate.

The good news is the blue line; in that large sub-group of 35%, the kids had some kind of “dysmaturation” at time 1, allowing them to make rapid cognitive improvement in the 4 years after their diagnosis (Time 1). They have gone from a technical definition of MR/ID to getting close to average IQ.

It would be great to see what happens at Time 3. I suppose if we wait 4 years we may find out.

I think some of the 35% (blue line) likely did not perform to their full ability at the first test (at time 1), for which there are numerous reasons, not liking/being familiar with the tester being an obvious one.  Based on other sources from this blog, I think it is about 15% of autism cases that make such a dramatic improvement to the age of eight.

In the above study the type of intervention chosen by parents (how many hours of ABA, speech therapy etc) had no correlation with IQ improvement from Time 1 to Time 2. It is your biology that matters most and to tweak that you need a little help from chemistry, as some regular readers have discovered. 

Counter Argument 

There is a alternative view that IQ is not important in ensuring favorable outcomes in autism; this does sound rather odd. It is a view put forward not just by the small, but vocal, group with Asperger's promoting their "neurodiversity" ideas, but also some well paid researchers. In my chart above I used Asperger's for the black line representing the people with average IQ. In the actual paper they do not call it Asperger's.

Intelligence scores do not predict success for autistic adults 

This is a very recent, rather light weight, article and would be much better if titled "Intelligence scores do not predict success for Aspies."   

Aspies do indeed share some biological problems with people with severe autism, but their daily life problems are much closer to those faced by people with Schizophrenia or Bipolar. A good example is suicide, where it is extremely common in bipolar, said to be 10% (as cause of death) in schizophrenia and ten times the "normal" level in Asperger's.  In severe autism the suicide rate is zero, they may have accidents but do not try to kill themselves.

In someone with Asperger's and an IQ of 120, boosting their IQ to 140 will likely not help them; it would just make them feel more different. In a ten year old with severe autism and an IQ of 50, a child who cannot figure out which way round to put on his T shirt, cannot tie his shoelaces and does not understand why you need to cut your finger nails, a boost in IQ to 80 would be transformative. 

The education of people with severe autism focuses on adaptive behavior, or life skills. These are key skills for semi-independent living. These are skills that children of average IQ just pick up from observing the people around them. People with impaired cognitive function cannot just pick up these skills, they need to be taught (again and again and again).  I spent three years trying to teach prepositions to my son Monty to the age of eight, using a special computer program created for other people with exactly the same difficulty. Once I started addressing cognitive function, with Bumetanide, from the age of 9, Monty figured out prepositions all by himself, without any teaching. I never even bothered to use the remaining language teaching software that I had paid $1,500 for, as a bundle, when he was four years old.  It is still sitting unopened on the shelf.