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Thursday 9 November 2017

Variable Expression of GABRA5 and Activation of α5 -  a Modifier of Cognitive Function in Autism?


Today’s post sounds complicated. We actually already know that the gene GABRA5, and hence the alpha 5 sub-unit of GABAA receptors, can affect cognition, but we do not know for sure in whom it is relevant.
Most readers of this blog are lay people, as such we tend to be predisposed to the idea that autism is somehow “hardwired”, something that just happened and cannot be reversed. Some of autism is indeed “hardwired”, you cannot take an adult with autism and “re-prune” his synapses, to produce a more elegant robust network in his brain. But much can be done, because many things in the brain are changing all the time, they are not fixed at all. Today’s post is good example.
GABA is the most important inhibitory neurotransmitter in the brain. There are two types of GABA receptor, A and B. These receptors are made up of sub-units. There are many different possible combinations of sub-units to make GABAA receptors. These combinations are not fixed, or “hard-wired”; they vary all the time.
The composition of the GABAA receptor changes its effect. It can change how you feel (anxiety) and it can change you think/learn.
You can actually measure GABRA5 expression in different regions of the brain in a test subject using a PET-CT (Positron Emission Tomography–Computed Tomography) scan and it has been done in some adults with high functioning autism. This machine looks like a big front-leading washing machine, just a bit cleverer. 

our primary hypothesis was that, compared to controls, individuals with ASD have a significant reduction in α5 GABA receptor availability in these areas.
Due to the small sample size, we could not examine possible correlations between GABAA binding and particular symptoms of ASD, age, IQ, or symptoms of comorbidities frequently associated with ASD, such as anxiety disorders, OCD and depression. We were also unable to address the effects of possible neuroanatomical differences between people with ASD and controls, which might lead to partial volume effects in PET studies. However, the modest magnitude of the volumetric differences seen in most studies of high-functioning ASD suggests that it is unlikely that these could fully explain the present findings.

These preliminary results suggest that potentiation of GABAA signaling, especially at GABAA α5-subunit containing receptors, might potentially be a novel therapeutic target for ASD. Unselective GABAA agonists and positive allosteric modulators, such as benzodiazepines, have undesirable features such as abuse potential and tolerance, but more selective modulators might avoid such limitations. Further research should extend this work in a larger sample of ASD individuals. It would also be interesting to use PET with the ligand [11C]Ro15-4513 to measure GABAA in disorders of known etiology characterised by ASD symptoms, such as Fragile X and 15q11-13 duplication
In summary, we present preliminary evidence of reduced GABAA α5 expression in adult males with ASD, consistent with the hypothesis that ASD is characterised by a defect in GABA signaling. 

The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABAA receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the α5 subunit of the GABAA receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the α5GABAA receptor-anchoring protein radixin, further supporting a α5GABAA receptor deficiency in ASDs.

The results from the current study suggest that drugs that act as positive allosteric modulators of α5GABAA receptors may ameliorate autism-like behaviors 
  

Too many or too few the α5GABAA receptors or too much/little activity?

Regular readers will know that autism is all about extremes hypo/hyper, macro/micro etc. The same is true with α5GABAA, too few can cause autistic behaviors, but too many can impede learning. You need just the right amount.
The next variable is how well your α5GABAA are behaving, because even if you have an appropriate number of these receptors, you may not have optimal activity from them. Over activity from α5GABAA is likely to have the same effect as having too many of them.
Here it becomes very relevant to many with autism and inflammatory comorbidities, because systemic inflammation has been shown to activate α5GABAA. It has been shown that increased α5GABAA receptor activity contributes to inflammation-induced memory deficits and, by my extension, to inflammation-induced cognitive decline.

α5GABAA Receptors Regulate Inflammation-Induced Impairment of Long-Term Potentiation


Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABAA) receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABAA receptor function. A tonic inhibitory current generated by α5GABAA receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABAA receptors in the hippocampus. Collectively, these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.


We saw in an earlier post that overexpression of GABRA5 is found in slow learners and we know that this is a key target of Down Syndrome research, aimed at raising cognitive function.

What can be modified?
It appears that you can modify the expression of GABRA5, which means you can increase/decrease the number of GABAA receptors that contain an α5 subunit.
You can also tune the response of those α5 subunits. You can increase it or decrease it.
Activation of the α5 subunit is thought to be the reason why benzodiazepine drugs  have cognitive (reducing) side effects. By extension, inverse agonists of α5 are seen as likely to be nootropic.
One such drug is LS-193,268  is a nootropic drug invented in 2004 by a team working for Merck, Sharp and Dohme.
A complication is that you do not want to affect the α2 subunit, or you will cause anxiety. So you need a highly selective inverse agonist.
The new Down Syndrome drug, Basmisanil, is just such a selective inverse agonist of α5.
Basmisanil (developmental code names RG-1662, RO5186582) is a highly selective inverse agonist/negative allosteric modulator of α5 subunit-containing GABAA receptors which is under development by Roche for the treatment of cognitive impairment associated with Down syndrome.  As of August 2015, it is in phase II clinical trials for this indication.


A contradiction
As is often the case, there is an apparent contradiction, because on the one hand a negative allosteric modulator should be nootropic in NT people and appears to raise cognition in models of Down Syndrome; but on the other hand results from a recent study suggests that drugs that act as positive allosteric modulators of α5GABAA receptors may ameliorate autism-like behaviors.
So which is it?
Quite likely both are right.
It is exactly as we saw a long while back with NMDAR activity, some people have too much and some have too little. Some respond to an agonist, some to an antagonist and some to neither.
What we can say is that fine-tuning α5GABAA in man and mouse seems a viable option to enhance cognition in those with learning difficulties.
The clever option is probably the positive/negative allosteric modulator route, the one being pursued by big Pharma for Down Syndrome.
I like Dr Pahan’s strategy from this previous post, for poor learners and those with early dementia

to use cinnamon/NaB to reduce GABRA5 expression, which has got to consequently reduce α5GABAA activity.
All of these strategies are crude, because what matters is α5GABAA activity in each part of the brain. This is why changing GABRA5 expression will inevitably have good effects in one area and negative effects in another area. What matter is the net effect, is it good, bad or negligible?
The fact that systemic inflammation increases α5GABAA activity may contribute to the cognitive decline some people with autism experience.
We previously saw how inflammation changes KCC2 expression and hence potentially increases intra cellular chloride, shifting GABA towards excitatory.
Ideally you would avoid systemic inflammation, but in fact all you can do is treat it.
Increasing α5GABAA activity I would see as possible strategy for people with high IQ, but some autistic features.
I think those with learning problems are likely to be the ones wanting less α5GABAA activity.
The people for whom “bumetanide has stopped working” or “NAC has stopped working” are perhaps the ones who have developed systemic inflammation for some reason.  You might only have to measure C-reactive protein (CRP) to prove this.




More reading for those interested:-










Wednesday 1 November 2017

OAT3 inhibitors for Bumetanide - Probenecid, but also Aspirin, Chlorogenic acid (Coffee), Epicatechin (Cocoa, Cinnamon) and more.


Today’s post is about OAT3, highlighted by the green lines.
The interventions reduce renal excretion and raise plasma
concentration rather than directly improving transport across the BBB

Today’s post is a collaboration. Our reader Ling pointed out research trying to boost the bioavailability of bumetanide using something clever called an OAT3 inhibitor.  This would reduce the rate at which the body excretes bumetanide and thus potentially improve its therapeutic effect.
Petra, our reader from Greece, pointed out that in her son Bumetanide seemed to work better when taken with Greek coffee and that that Greek Grandpas like to take their diuretics with a steaming Greek coffee.
Most people, me included, automatically think caffeine when someone mentions coffee.
So I assumed that caffeine might be an OAT3 inhibitor and I did make some experiments on that basis. There is no research data to support caffeine as an OAT3 inhibitor.
Recently I was again looking for other potential Bumetanide boosters.  The obvious one is called Probenecid.  Probenecid is used to treat gout because it lowers uric acid.
Aspirin has some odd effects; low dose aspirin will raise uric acid, but high dose aspirin will lower it. Aspirin is an OAT3 inhibitor.
OATs are a very niche subject, to add to the confusion sometimes you are better looking for SLC22A8, the gene that encodes the transporter. 
There was an earlier post on this subject, which showed that many NSAIDs inhibit OAT3, including Knut’s favourite Ponstan. They are not so well suited to continued use.

At the end of my little investigation I figured it out; there are many OAT3 inhibitors available, including some in your kitchen.  


Key points on OAT3 (Organic Anion Transporter 3)
If you want to increase the peak concentration and indeed the half-life of a drug that is excreted from the body by OAT3 (organic anion transporter 3), an OAT inhibitor is what you need.
The drug Probenecid is by far the best known OAT3 inhibitor and it is very potent. It has long been to boost the performance of penicillin type antibiotics to treat tough bacterial infections.
Probenecid, if available, may very well be the ideal bumetanide booster.
For adults a simple option is Greek/Turkish coffee. I see little downside as long as you can handle the caffeine. The Greeks live a long time and drink plenty of coffee.
For those who do not like caffeine you can go to active components within the coffee, which seem to be the chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid). They are sold as a weight loss supplement, the long established version is the French-made Svetol, but there are now others. They still contain 2- 3% caffeine.
Epicatechin, found in cinnamon, dark chocolate and high flavanol cocoa is another OAT3 inhibitor. Cocoavia, made by Mars, is used by some readers of this blog. Cocoa flavanols do clever things with nitric oxide (NO) and have been shown to improve mild cognitive impairment (MCI) and heart health by improving blood vessel elasticity.
Catechins are flavanols belonging to a family of closely related compounds, such as epicatechin, epigallocatechin, epicatechin gallate (EGC), and epigallocatechin gallate (EGCG). They are all slightly different. Catechin itself is not an OAT3 inhibitor; EGCG may or may not be.
Low dose aspirin is likely the cheapest OAT3 inhibitor. It also increases peripheral circulation, which could benefit some. Low dose aspirin has the downside of a small bleeding risk, mainly in old people, and there is a risk of Reye’s syndrome if given during/after a viral infection.
I think for adults a Greek coffee may be the best. For people who have a profound benefit from Bumetanide, I think they should look into Probenecid.
Personally I think Svetol is worth a try.
Coffee that has been extensively processed (just as we saw with cocoa) may not have the same chlorogenic acid content as the more gritty coffee used in the Balkans. Coffee consumption is actually associated with many neurological benefits, reducing the incidence of Parkinson’s and Alzheimer’s; the common mistake in research is the assumption that the effect must be from caffeine.











  
The health effects of decaffeinated Coffee
My eureka moment in this post was reading about gout and coffee and then decaffeinated coffee. 




So then it was a question of finding what in coffee could be the OAT3 inhibitor. At which point I found a very insightful paper that tells you everything, once you realise that:

Coffee = chlorogenic acids  = 1,3- and 1,5-dicaffeoylquinic acid


Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions

3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids

Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus  pmol mg 10  , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.










Lay off the Lycopene?
Lycopene does the opposite of what we want. Too much lycopene may lower the effectiveness of a drug that is excreted via OAT3. 

2.29. Lycopene

Lycopene is a carotenoid pigment found in tomato [94]. Lycopene from dietary sources has been shown to reduce the risk of some chronic diseases including cancer and cardiovascular disorders [95]. The administration of lycopene significantly normalized the kidney function and antioxidant status of CSP-treated animals. Furthermore, lycopene also increased the expression of the organic anion and cation transporters (OAT and OCT, resp.) including OAT1, OAT3, OCT1, and OCT2 in the renal tissues [9698]. In addition, lycopene also decreased the renal efflux transporters (multidrug resistance-associated protein [MRP]-2 and MRP4) levels and induced Nrf2 activation, which activated the antioxidant defense system [99]. Furthermore, lycopene protected against CSP-induced renal injury by modulating proapoptotic Bax and antiapoptotic Bcl-2 expressions and enhancing heat shock protein (HSP) expression [97].

https://www.hindawi.com/journals/omcl/2016/4320374/                                                                                                                  

Aspirin
I actually started out this post by looking at what dose of aspirin might be effective in inhibiting OAT3.  We do know that Aspirin is indeed an OAT3 inhibitor.  


I did find the answer, but along the way you do end up having to look at uric acid. 
Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1 Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1. 
Uricosuric drugs increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. 
In general, uricosuric drugs act on as urate transporter 1 (URAT1). URAT1 is the central mediator in the transport of uric acid from the kidney into the blood.  By their mechanism of action, some uricosurics (such as  probenecid) increase the blood plasma concentration of certain other drugs and their metabolic products  – this is their effect on OAT3.
Probenecid is a medication that increases uric acid excretion in the urine.
Atorvastatin is a so-called secondary uricosuric. High dose aspirin should also be called a secondary uricosuric.
Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics and low dose aspirin. 
Low dose aspirin inhibits OAT1 and OAT3 which reduces urate secretion, but high dose aspirin inhibits URAT1 and reduces urate re absorption. This is sometimes known as the biphasic effect.
So low dose aspirin will increase plasma uric acid, but high dose aspirin has the same effect as Probenecid, it lowers plasma uric acid levels.
So Aspirin and Probenecid both affect URAT1 and OAT3. 






At what dose is Aspirin an OAT3 inhibitor?
If we just want aspirin to inhibit OAT3 and not inhibit URAT1, what dose is effective? Fortunately this has been answered in the research. The typical low dose of aspirin (75mg) used preventatively in older people is OAT3 inhibiting, it raises plasma uric acid.  





Salicylate

Salicylic acid and its derivatives are the most prescribed analgesic, antipyretic, and anti-inflammatory agents. Salicylates have a “paradoxical effect” on the handling of uric acid by the kidney. The action of salicylates on uric acid excretion depends on the dose of salicylates. At doses of less than 2.5 g/day, salicylates cause the retention of uric acid by blocking the tubular secretion of uric acid, while at dose of higher than 3 g/day, they cause increased urinary excretion of uric acid [70]. Mini-dose aspirin, even at a dosage of 75 mg/day, caused a decrease in uric acid excretion and raised serum uric acid level [71]. It has been suggested that the “paradoxical effect” of salicylate can be explained by two modes of salicylate interaction with URAT1: (1) acting as an exchange substrate to facilitate uric acid reabsorption, and (2) acting as an inhibitor for uric acid reabsorption [72]. Low dose of salicylate interact with OAT1/OAT3, the uric acid secreters [73].

Low dose aspirin leads to decreased renal excretion of uric acid and raised serum uric acid levels, which can cause a gout attack in those predisposed to this condition.
High doses of aspirin lower serum uric acid concentration.

Reye’s Syndrome
In children aspirin is very rarely used because of the risk of Reye’s syndrome. Reye’s syndrome causes severe liver and brain damage. It is a type of severe mitochondrial failure that can occur after a viral infection like flu or chickenpox, but it almost only occurs when aspirin has been prescribed. Nobody knows for sure the exact mechanism of the disease.
So do not give aspirin to children with a viral infection.  We already know to avoid paracetamol/acetaminophen (Tylenol in the US) in babies/children and people with autism. Paracetamol/acetaminophen depletes the body’s key antioxidant GSH. 
If someone overdoses on Paracetamol/acetaminophen you give them a high dose of NAC to prevent death. 


Conclusion
Given how long it takes to develop new drugs, I think that improving the pharmokinetics of bumetanide is a pretty obvious thing to do. 
Diamox is an OAT3 inhibitor and our reader Agnieszka found it beneficial only when administered along with Bumetanide.
Strong coffee is an OAT3 inhibitor and this was found to enhance bumetanide by Petra’s son with Asperger’s.
Cinnamon which contains epicatechin, another OAT3 inhibitor, did seem to be helpful in Monty who also takes bumetanide.
I suspect Diamox may be the most potent OAT3 inhibitor of those three
The interesting OAT3 inhibitors seem to be:-

·        Probenecid

·        Low dose aspirin

·        Epicatechin (cocoa, cinnamon ..)

·        Chlorogenic acids (coffee and decaffeinated green coffee extracts) 

Cinnamon, high flavanol cocoa and indeed coffee (minus the caffeine) have numerous health benefits.
Note that Catechin has no effect on OAT3. EGCG was not tested but in other studies has been shown it does affect.



The logical next step would be to improve bumetanide transport across the blood brain barrier.










Tuesday 24 October 2017

Treated ID and CBS/DYRK1A in Autism and Down Syndrome

One of the most interesting concepts I have come across writing this blog is the idea of treating people with mental retardation (MR) / intellectual disability (ID). I do keep using the term MR, because 90% of the world has no idea what ID means. MR is a very precise description, which is increasingly rare these days.
I still recall several years ago going to a French-speaking neighbour’s barbecue. The French are generally very family-oriented, but quite traditional when it comes to parenting, (hence their low rates of ADHD diagnosis). At that time, Monty aged around 8, could act strangely and was rather obsessed with fire, matches and cigarette lighters. Our neighbour introduced us to his French friends and explained Monty with a brief use of the word “retardé”, which did not prompt any comments or requests for clarification. In the English language this might have been regarded as a big faux-pas; it did not bother me.  It seemed to work very well to forewarn people not to over-react to any unexpected behaviours. 
In the English language, autism has become a nice word and seems the new ADHD, with people even wanting to be diagnosed with it.  MR/ID is still something reserved for other people; it is not something most people want to be associated with. I do use the term cognitive dysfunction, which is just as explicit as MR but does not seem to upset people.
Cognitive dysfunction (MR/ID) is an inevitable consequence of more severe autism and it is just a question of degree. It is not a comorbidity, it is all part of the same package.

In Down Syndrome (DS) IQ is usually between 45 and 71 and worsens with age. MR/ID is defined as an IQ less than 70 and accounts for 2.3% of the general population. An IQ of 100 would put you in the middle of the IQ bell curve. People with DS tend to be very happy and contented, without the problematic behaviors that can occur in autism. 
The good news is that cognitive dysfunction (MR/ID) is likely to be treatable, as some readers of this blog have discovered. You just need to figure out how, which in itself is more about your perseverance than your IQ. You do not need to be an Einstein (IQ > 160), rather a marathon runner.
I just had the uncanny experience at school during the parent-teacher meetings, to be told that other class members could learn from my younger son Monty, aged 14 with autism; that he has the neatest handwriting in class, his essay had the best structure and that when his geography teacher told his assistant to skip the final question in the test (using longitude and latitude) because it was hard, the assistant said just let him try it; he was the only one to get it right. 
So from aged 8 to 14 he has gone from “retardé” to being something quite different.  The teachers do love his assistants, who are great; but he has had an assistant from the age of 4 and back then things moved forward extremely slowly. He learnt to read and write the very hard way, with a vast amount of 1:1 instruction and the school was amazed when his then assistant taught him to read; I don’t think they expected it ever to happen. By treating cognitive dysfunction pharmacologically for five years normal learning became possible and remains a big surprise to everyone.  His new English teacher knows him from back in the darker old days and seemed more shocked than surprised, after a month of teaching him. "Is this the same boy?"
For the first time at school I am being told to be proud of my younger son’s academic achievements, rather than how talented my older son is. Big brother certainly did not expect such a day and his response was along the lines of “well the others in his class must be really thick then” (like it or not, this is a typical teenage male comment). Little brother still has autism, but it is much less disabling. Big brother is currently teaching him to fence (sword fighting), which he would not have bothered to try doing until recently, because it would not have ended well. Years ago Monty did learn to ski, play basketball and soccer, but that all took a lot of effort with very patient (mostly female) instruction; he initially had no idea what to do if a ball was rolled towards him.  Last week he happily sat through the new Blade Runner film, which is nearly three hours long with the trailers. 
Perhaps there is no need for further “breakthroughs” with my Polypill therapy.  It may be good enough already.
It just seems a pity that more people with cognitive dysfunctions are not treated. There are some extremely intelligent parents with children who have severe autism, indeed an ironic twist of genetics. Some even write autism research, or indeed fund it. Even these people are not treating it.   Their fear of quackery blinds them. There certainly are quacks and there are also those who straddle the line, some of what they say is nonsense, but other ideas may not be.

Imagine having a conversation with Bill Gates, who is using his billions to use vaccines to save millions of lives in poor countries, about the possibility that in some people vaccines might trigger mitochondrial disease and autism.  Any organization talking about autism in relation to vaccines, chelation, aluminium, heavy metals etc and anyone who associates with them are in effect blacklisted.
Why does the global head of neuroscience at Novartis not attend the Autism One or TACA conferences? He does have a son with severe autism. It would be very difficult for him to apply any therapy promoted by anyone who attends these events.
Why does a Professor of Medicine from the US Ivy League apply ideas from this blog to his son, but never leave a comment? It is very clear to me why.
As our reader Roger has commented, why do some leading autism researchers still go on about vaccines? It does their interests much more harm than good. 
I think Roger could teach Dr Naviaux a thing or two about getting his Suramin research funded.  


Enhancing Cognition
The first area I came across where serious research is underway to treat MR/ID concerns RASopathies, a group of disorders that share disturbed levels of a protein called RAS. It was actually French research.
In Down Syndrome (DS) I highlighted research that aims to increase cognitive function by targeting the alpha 5 subunit of the GABAA receptor. We also saw that the same abnormal level of chloride within in cells that exists in much autism also occurs in Down Syndrome (DS); this is why the Frenchman Ben Ari has patented Bumetanide as a therapy for DS. 
In schizophrenia and bipolar there is also reduced cognitive function, but only in schizophrenia has there been much research and clinical trials to improve it. Histamine receptors were one target of this research. 

Too much or too little CBS (Cystathionine-β-synthase )
One known cause of cognitive dysfunction that has not been mentioned in my posts is CBS and since it was raised in a comment I thought it should be included.
All you need to know if you want to rule out a CBS problem is your level of homocysteine. If it is normal you do not have a problem with CBS. If homocysteine is high you have a case of Hyper-homocystinuria, which may be caused by too little CBS, or for a different reason. If you have very low levels of homocysteine (Hypo-homocystinuria) that may be caused by too much CBS and if you have Down Syndrome elevated CBS is inevitable.
Normalizing CBS is very likely to help cognition.
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:

L-serine + L-homocysteine    <------>     L-cystathionine + H2O


Down syndrome is a medical condition characterized by an overexpression of cystathionine beta synthase (CBS) and so a low level of homocysteine in the blood. It has been speculated that cystathionine beta synthase overexpression could be the major culprit in this disease (along with dysfunctioning of GABAA and Dyrk1a). The phenotype of down syndrome is the opposite of Hyperhomocysteinemia (described below). Pharmacological inhibitors of CBS have been patented by the Jerome Lejeune Foundation and trials are planned.


Down's syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation, and adults with DS develop Alzheimer type of disease (AD). Cystathionine beta-synthase (CBS) is encoded on chromosome 21 and deficiency in its activity causes homocystinuria, the most common inborn error of sulfur amino acid metabolism and characterized by mental retardation and vascular disease. Here, we show that the levels of CBS in DS brains are approximately three times greater than those in the normal individuals. CBS is localized to astrocytes and those surrounding senile plaques in the brains of DS patients with AD. The over-expression of CBS may cause the developmental abnormality in cognition in DS children and that may lead to AD in DS

It is a French foundation that is funding research is develop CBS inhibitors to improve cognition in Down Syndrome.


NovAliX will use its expertise and capabilities in medicinal chemistry and structural biology to develop small molecule lead candidates targeting the cystathionine-beta-synthase (CBS). Indeed inhibition of CBS over-expression has been associated with restoration of cognitive impairment in animal models afflicted with trisomy. 

People with DS have a low incidence of coronary atherosclerotic disease (CAD), which would seem to be linked to their low level of homocysteine (high CBS), but their high level of DYRK1A (see later) may be the cause of their early onset Alzheimer’s. 
Some background on homocystinuria, courtesy of Wikipedia:- 

Classical homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase.
Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of the amino acid homocysteine in the serum and an increased excretion of homocysteine in the urine.
Signs and symptoms of homocystinuria that may be seen include the following:


The term homocystinuria describes an increased excretion of homocysteine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine sythase deficiency, MTHFR) and vitamin deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9) deficiency, riboflavin deficiency (vitamin B2), pyridoxal phosphate deficiency (vitamin B6)). In light of this information, a combined approach to laboratory diagnosis is required to reach a differential diagnosis.  

DYRK1A
You may have noticed that DYRK1A was mentioned as another cause of cognitive loss in Down Syndrome.  DYRK1A is yet another autism gene; it encodes an enzyme that is important in how the brain develops. Too much DYRK1A also leads to reduced levels of homocysteine. 
An OTC DYRK1A inhibitor exists today, epigallocatechin gallate (EGCG).



DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases

Neurodevelopmental alterations and cognitive disability are constant features of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations. Treatment of Dyrk1A transgenic mice with epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance, suggesting that EGCG may represent a suitable treatment of DS. Evidence in the Ts65Dn mouse model of DS shows that EGCG restores hippocampal development, although this effect is ephemeral. Other studies, however, show no effects of treatment on hippocampus-dependent memory. On the other hand, a pilot study in young adults with DS shows that EGCG transiently improves some aspects of memory. Interestingly, EGCG plus cognitive training engenders effects that are more prolonged. Studies in various rodent models show a positive impact of EGCG on brain and behavior, but other studies show no effect. In spite of these discrepancies, possibly due to heterogeneity of protocols/timing/species, EGCG seems to exert some beneficial effects on the brain. It is possible that protocols of periodic EGCG administration to individuals with DS (alone or in conjunction with other treatments) may prevent the disappearance of its effects.


Conclusion

Understanding emerging therapies that treat various types of MR/ID, and also the various types of dementia, should unlock interesting avenues to raise cognitive function in many types of autism.
Homocysteine levels are very easy to measure. 
Because the gene miss-expression in Down Syndrome (DS) is fully understood, it makes sense that treatment is more advanced than in autism, which is so heterogenous. There are a lot of people in the world with DS and so there is a big market for drug makers.
The potential drug therapies to improve cognition in Down Syndrome (DS) appear to be:- 

·        Basmisanil, a negative allosteric modulator of α5 subunit-containing GABAA receptors. It appears that sodium benzoate may have a similar effect.

·        Bumetanide, an NKCC1 inhibitor

·        Potassium bromide, Br- displaces Cl- to lower intracellular Cl-

·        CBS inhibitor

·        DYRK1A inhibitor, like Epigallocatechin gallate (EGCG), but a more potent inhibitor like CX-4945 (Silmitasertib) might be better.

There is mouse model research to show that a single dose just after birth of a drug that stimulates the sonic hedgehog signaling pathway results in a "normal" adult brain.

The risk of Down Syndrome (DS), caused by a third copy of chromosome 21 (trisomy 21), rises rapidly with increasing maternal age, nonetheless the number of births is stable to falling in most developed countries, due to increased prenatal testing and termination of pregnancy for fetal anomaly (TOPFA). TOPFA is not practiced in countries like Poland and Ireland. In Denmark screening has long been free and TOPFA has risen to 98%. In the UK two thirds of mothers opt for their free DS screening and 90% of those who test positive, opt for their free TOPFA. The one third letting nature take its course are probably mainly younger mothers.
In Catholic countries you have both extremes - in Cork, Ireland DS is present 30 times per 10,000 births, but in Zagreb Croatia it is just 6 per 10,000. In the US the CDC say it 14, while in the UK it is 10.  In South Africa 20 cases of DS occur per 10,000 births; mothers are younger than in Ireland.
In developed countries, the natural prevalence of DS looks to be 0.3%, which is the same as the incidence of strictly defined autism (SDA), which I estimated in an earlier post to be 0.3%. It is just that in developed countries most people with DS are never born. 

I would have thought CX-4945 should be trialed by some clever Alzheimer's researcher and indeed for any Tauopathy. In the meantime perhaps Grandad should drink a lot of green tea to get his dose of EGCG.