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Showing posts with label Simvastatin. Show all posts
Showing posts with label Simvastatin. Show all posts

Thursday 22 June 2023

Autism Research Merry-go-round Keeps Turning

 


Today’s post again shows that many issues raised in previous posts keep on coming back  is that good news? Only you can decide.

I start with the “old chestnut” (English idiom to imply “a tired old story”) of the Autism Tsunami. 

Then we see what has come up in the world of autism interventions in the research in the last 3 weeks, most of which regular readers will already be aware of.

·        Autism Tsunami – real or not?

·        Vitamin D

·        Bumetanide

·        Ibudilast

·        Niclosamide

·         Non-invasive brain stimulation

·         Simvastatin 

I noted the research about autism incidence coming from Northern Ireland because it was published in the Belfast News Letter.  These days it has a tiny subscription, but I am one of those who know it is the world's oldest English-language general daily newspaper still in publication, having first been printed in 1737. In 1972 a bomb warning was called in to the paper's office and, as people evacuated, an explosion went off nearby killing several people and injuring many more. Back in the early 1990s, when some people in Northern Ireland were still blowing up others with bombs, I made a visit to Northern Ireland to meet the management of this newspaper. 

Their recent article on autism incidence is very well researched considering how only about 8,000 copies are published. Keep up the good work!

Idea that 5% of all Northern Ireland's children are autistic is 'a fantasy' claims international expert

Professor Laurent Mottron was speaking to the News Letter following a claim that the rate of autism in Northern Ireland is double the rate in the rest of the UK.

Back in 2019 Prof Mottron had authored a report warning about a tsunami of over-diagnosis, saying that soon "the definition of autism may get too vague to be meaningful, trivializing the condition"

“If this trend holds, the objective difference between people with autism and the general population will disappear in less than 10 years," he had said then – and has now indicated that this “fuzziness” is what’s helping swell the numbers in Northern Ireland.

Meanwhile Jill Escher, the president of the National Council on Severe Autism, takes a different view.

She says that evidence indicates the "skyrocketing" rate of autism in Northern Ireland is real, adding: "It boggles my mind that it is not the subject of the highest possible alarm and inquiry."

"One in 20 children in Northern Ireland of school age has a diagnosis of autism," he told MPs.

"[It is] one in 57 in the rest of the UK. The need in Northern Ireland is significantly different."

To put that in perspective, that would mean 5% of Northern Irish children are diagnosed with autism, compared with 1.8% in the rest of the UK.

Prof Mottron, a psychiatrist based at Montreal University, told the News Letter "numbers such as 5% are pure fantasy... these numbers correspond to the part of the general population which has less overt socialisation, which has minimally to do with prototypical autism". 

There is a "current fuzziness of autism diagnosis and over-inclusivity," he said, leading to "a situation of perfect confusion between autistic traits and prototypical autism" (that is, mixing up people who exhibit some tendencies of autistic people with people who actually have the full-blown condition). 

"The scientific 'quasi consensus' would be around 1% everywhere on the planet,” he added.

 

So on one side we have Jill Escher and her NCSA and on the other we have a French/Canadian researcher.  This time Laurent Mottron but in my blog posts I quoted Éric Fombonne.

A paper that was mentioned both in my blog and critiqued by Jill about autism incidence and cost just got retracted.  In reality a better word is “cancelled.”  The 3 authors are very much in the politically incorrect camp of the autism debate.

I was surprised it ever got published.  

Controversial ‘cost of autism’ paper retracted 

Citing methodological issues and undeclared conflicts of interest, an autism journal has retracted a paper that forecast the prevalence and cost of autism.

The retraction note, posted last week, comes two years after Spectrum reported on backlash surrounding the paper, which was published in the Journal of Autism and Developmental Disorders in July 2021. A month after publication, the journal added an editor’s note that the study was under investigation because of criticisms of its conclusions. 

“I am glad to see that it was retracted, although at a pace that maybe is a bit frustrating in terms of how long it took. But it was the right choice,” says Brittany Hand, associate professor of health and rehabilitation sciences at Ohio State University in Columbus.

Outside experts who reviewed the paper on the journal’s behalf found that it misrepresented the rise in autism diagnoses and gave “insufficient attention” to some potential causes of the increase, such as improved surveillance and changes to the diagnostic criteria. The authors also used “higher estimates and assumptions that inflated costs,” according to the retraction note.

The authors — Mark Blaxill, Toby Rogers and Cynthia Nevison — all disagree with the journal’s decision, the note also says.

The cancelled paper is here:-

Autism Tsunami: the Impact of Rising Prevalence on the Societal Cost of Autism in the United States

 

I assume Blaxill was the driving force behind all the math, because he is the ex- management consultant, with a son with severe autism that his dad attributes to vaccines.

What I found bizarre in their paper was that they has a prevention scenario, based on what they think has already happened in rich parts of California, where they think autism incidence is falling.  It is not falling, all that is happening is that wealthy Californians are paying for treatment using insurance or their own money, and no longer burdening the State.

The “rainbow” researchers that wanted the paper retracted think that preventing autism is akin to eugenics and Dr Mengele. According to Peter, treating autism is good, while Dr Josef Mengele, byname Todesengel (German: “Angel of Death”) was as bad as you can get.    

Jill Escher and her NCSA think that you cannot prevent autism.  According to Peter, you can both minimize the incidence and severity of autism. 

A bugbear of our reader Tanya is that the NCSA have a pet hate of facilitated communication and in particular the rapid prompting method (RPM). This method worked for Tanya’s son and it opened the door to independent, un-facilitated communication. 

Always keep an open mind.

 

 

 

“our Prevention scenario is based on real rates observed among wealthy white and Asian children in the California DDS.  Severe ASD prevalence has flattened and even declined among these children since birth year 2000, suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD. The Prevention scenario assumes that these parental strategies and opportunities already used by wealthy parents to lower their children’s risk of ASD can be identified and made available rapidly to lower income children and ethnic minorities, who are currently experiencing the most rapid growth in ASD prevalence”

 

New Paper Makes Case that Autism Tsunami May Threaten American Economy

A major weakness in the analysis was the “Prevention Scenario” in which future costs were projected based on “what might be possible if strategies for reducing ASD risk are identified and addressed in the near future.” As I think everyone knows, at this time there is no way to prevent autism. But the authors use the observation that autism in the DDS is declining among wealthier white families, and thus “suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD.” No, it’s far more likely that wealthier families are not entering their children into the system because they access services through insurance and school districts instead.

 

Vitamin D as a cause of autism has been discussed for decades.  As the title below puts it – a never-ending story. Our reader Seth Bittker even wrote a paper about it. He later wrote a paper about the use Acetaminophen/Paracetamol in children under two as a risk factor in developing autism. Good work Seth!

 

Maternal Vitamin D deficiency and brain functions: a never-ending story 

A large number of observational studies highlighted the prevalence rates of vitamin D insufficiency and deficiency in many populations as pregnant women. Vitamin D is well known to have a crucial role in differentiation and proliferation, as well as neurotrophic and neuroprotective actions in brain. Then, this micronutrient can modulate the neurotransmission and synaptic plasticity. Recent results from animal and epidemiological studies indicated that maternal vitamin D deficiency is associated with a wide range of neurobiological disease including autism, schizophrenia, depression, multiple sclerosis or developmental defect. The aim of this review is to provide a state of the art on the effect of maternal vitamin D deficiency on brain functions and development.

4.2.2. Autism

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with repetitive behaviour and difficulties in social interaction, communication and learning. Several murine studies and cohorts have demonstrated that early exposure to low levels of VD during pregnancy could be a risk factor for ASD. In 2019, Ali et al. aimed to find out the impact of a maternal VDD on early postnatal, adolescent and adult offspring. By assessing righting reflex and negative geotaxis, they found out that the pups from deficient dams showed a delay in their motor development. P12 rats from deficient females also exhibited increased ultrasound vocalization indicating an alteration in their vocal communication. Adolescent and young adult rats displayed an altered stereotyped repetitive behaviour as they had a reduced digging behaviour. Adolescent rats had less social interaction with longer latency to interact, which was not found in adult rats; however, adults were more hyperactive but showed no anxiety like behaviour.  In another animal study, maternal VDD induced an increase in the vocalizations of the pups accompanied with a decrease in cortical FoxP2, decrease in social behaviour and impaired learning and memory were observed in adult males (Table 1). Using data from the Stockholm youth cohort, Magnusson et al. examined a population of 4-17-year-old children exposed to low levels of VD during gestation and was able to report a positive association between maternal VDD and ASD. Analysing the same cohort, Lee et al. suggested that high levels of VD during pregnancy were associated with a moderate decrease in risk of ASD in the offspring. A prospective study of a multi-ethnic cohort in the Netherlands (generation R study) has also shown an association between maternal mid-gestation VDD and a two-fold increase in the risk of autism in children (Table 2). Interestingly, VD supplementation seems to clinically improve ASD symptoms of affected children.

 

People do associate this blog with Bumetanide.  Yet another paper has been published showing the benefits of this therapy for autism.

 

EEG-based brain connectivity analysis in autism spectrum disorder: Unravelling the effects of bumetanide treatment 


Highlights

 

·        We investigated the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment.

·        We found statistically significant differences between pre and post intervention in the connectivity patterns using repeated measures analysis of variance (ANOVA).

·        We found that the number of strong connections in response to sad image stimuli seem to be less compared with that of the other two stimuli, especially in the central area.

·        We found that the changes in brain connectivity between pre and post intervention is more significant in response to sad image stimuli.

 

Emerging evidence suggests that cognitive impairment associated with brain network disorders in people with autism could be improved with medications such as bumetanide. However, the extent to which bumetanide is effective in improving brain function in these individuals has not been adequately studied. The main purpose of this study is to investigate the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment. We used electroencephalography (EEG) data of nine participants recorded during the face emotion recognition activity in two stages before and after bumetanide treatment. Brain connectivity matrix was calculated using a neural network-based estimator. Graph criteria and statistical tests have been used to determine the effects of bumetanide treatment on children and adolescents with autism. Bumetanide treatment significantly alters the brain connectivity networks based on stimuli type. Differences in brain connectivity related to the sad stimuli are more significant. The most of the significant changes of the strength graph metric was in the occipital electrodes and electrodes related to the right hemisphere. These results suggest that bumetanide may affect effective connectivity and be used a promising treatment for improving social interactions in patients with autism. It also suggests that brain connectivity patterns can be considered as a neural marker to be used in the development of new therapies. 

I have also covered in sometimes painful details the potential to treat autism and increase cognitive function using PDE (Phosphodiesterase) inhibitors. One of our psychiatrist readers is a huge fan of Pentoxifylline and takes it himself.

I was recently asked how to obtain Ibudilast.  It is approved in Japan as an asthma drug. Sometimes it is called Ketas and you can get it from an “International Pharmacy” in Germany/Switzerland if you have a prescription. 

I also wrote about repurposing Roflumilast, which as Daxas is approved all over the world as a therapy for severe asthma (COPD). This drug at a 1/5th dose has been patented as a cognitive enhancer.

 

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder

 

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats.

Methods

Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum.


Key findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage.

Conclusions

Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

 

 

I have also written widely about repurposing certain anti-parasite medicines to treat autism. This is not because I think parasites cause autism, it is the secondary modes of action.

 

 

Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis

 

 

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer’s Disease and Parkinson’s Disease, as well as various cancers by targeting ERK/MAPK, it’s efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

 

Note that in earlier posts I explored RASopathies as potentially treatable types of intellectual disability (ID). We also have RAS-dependent cancers as a discrete treatable sub-type of cancer.


The ERK/MAPK pathway is known to interact with multiple genes that have been implicated in autism, and genome-wide association analysis of the same have supported these findings. As such, a dysregulation of this pathway has been found to result in many CNS disorders, including ASD-related syndromes, in many studies. These syndromes are collectively known as Rasopathies, due to the fact that the affected genes include those encoding for elements which function together with Ras, a G-protein responsible for activating ERKs (Levitt and Campbell 2009; Tidyman and Rauen 2009). It has been found that ASD is linked to the occurrence of many Rasopathies, and there have been multiple reports suggesting the possible relation of ERK/MAPK pathway defects with the incidence of ASD (Vithayathil et al. 2018; Aluko et al. 2021)⁠⁠. Moreover, a detailed study has found that single nucleotide polymorphisms (SNPs) in the ERK/MAPK-related genes are more common in subjects presenting with idiopathic ASD.

 

Niclosamide is an FDA-approved antihelminthic drug which is routinely used to treat tapeworm infections by inhibiting their mitochondrial oxidative phosphorylation and ATP production. In addition, it has long been known to have significant immunomodulating activity, and has been shown to inhibit a number of signaling pathways, including the Wingless-related integration site (Wnt)/β-catenin, nuclear factor kappa B (Nf-κB), signal transducer and activator of transcription 3 (STAT3), and mammalian target of rapamycin (mTOR) (Chen et al. 2018). However, while these targets are known to be rather well-characterized in terms of the effect that niclosamide has on them, there are also other targets, including the phosphoinositode 3 kinase/Akt (PI3K/Akt) and ERK/MAPK pathways, that are seen to be downregulated by the agent. Hence, given the possible relation of the ERK pathway in autism, there has been interest in the potential role of niclosamide in the management of the prognosis of ASD. This article aims to discuss the possible therapeutic benefit of niclosamide in the treatment of autism spectrum disorders.

 

Now I know that parents like the idea of treating autism with various gadgets you can strap on to your head  things like Transcranial Magnetic Stimulation (TMS). I must say I liked my old post on Photobiomodulation/cold laser/low level laser therapy.


Epiphany: Low Level Laser Therapy (LLLT) for Autism – seems to work in Havana


From China we have a new round-up paper, but the full text does not yet seem to be ready.

 

Non-invasive brain stimulation for Patient with Autism A Systematic Review and Meta-Analysis

Objective: To comprehensively evaluate the efficacy of non-invasive brain stimulation (NIBS) in patients with autism spectrum disorder (ASD) in randomized controlled trials (RCT),providing reference for future research on the same topic.

Methods:Five databases were searched (Pubmed,Web of science,Medline,Embase and Cochrane library) and track relevant references,Meta-analysis was performed using RevMan 5.3 software.

Results: Twenty-two references(829 participants) were included. The results of meta analysis showed that, NIBS had positive effects on repetitive and stereotypical behaviors, cognitive function and executive function in autistic patients. Most of the included studies had a moderate to high risk of bias, Mainly because of the lack of blinding of subjects and assessors to treatment assignment, as well as the lack of continuous observation of treatment effects.

Conclusions: Available evidence supports an improvement in some aspects of NIBS in patients with ASD. However, due to the quality of the original studies and significant publication bias, these evidences must be treated with caution. Further large multicenter randomized double-blind controlled trials and appropriate follow-up observations are needed to further evaluate the specific efficacy of NIBS in patients with ASD.


Unfortunately, the Chinese have concluded that most of these studies are not reliable. So no laser for me to go out and buy just yet.

No need to dent your bank balance with the next therapy.  We are back to one of the world's most prescribed and therefore affordable drugs, its Simvastatin (Zocor). 

There is masses of information in this blog about the potential to treat sub-types of autism with Atorvastatin, Simvastatin or Lovastatin. They are each slightly different.

 

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model 

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway. 

Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting. 

Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p < 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats. 

Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

  

Conclusion

What is the conclusion? Well, I could say give up reading the new research and just read my old posts.  It seems you are not going to miss very much.

Of course, back in the real world, it is true that things do take time to change and after a few decades the leap might be taken from the research to the doctor’s office.

There already is plenty of research on the causes of autism and what steps can be taken by those who want to treat aspects of it.  It is far from a complete picture, but it is enough to get started.  There are no guarantees of success, but if you want 100% certainty you will wait forever.








Wednesday 24 October 2018

Choose your Statin with Care in FXS, NF1 and idiopathic Autism


There are several old posts in this blog about the potential to treat some autism using statins; this has nothing to do with their ability to lower cholesterol. 

Statins are broadly anti-inflammatory but certain statins do some other particularly clever things. This led me to use Atorvastatin and Fragile-X researchers to use Lovastatin.


Fragile X is suggested by an elongated face and big/protruding ears; 
other features include MR/ID and autism.

I was recently forwarded a Scottish study showing why Simvastatin does not work in Fragile X syndrome, but Lovastatin does.
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E (see chart below). In people with Fragile X, they lack the FMR1 protein. Boys are worse affected than girls, because females have a second X chromosome and so a "spare" copy of the gene.


         Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.

So  ? = Does NOT inhibit

The researchers in Scotland did not test Atorvastatin in their Fragile X study.
The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

RASopathies have been covered in this blog. Too much of the Ras protein is a common feature of much ID/MR. Investigating RAS took me to PAK1 inhibitors and the experimental drug FRAX486. This drug was actually developed to treat Fragile X; it is now owned by Roche. At least one person is using FRAX486 to treat autism.
You might wonder why the researchers do not just try Lovastatin in humans with Fragile X.  Unfortunately, Lovastatin was never approved as a drug in Scotland, or indeed many other countries.  Some researchers just assumed they could substitute Simvastatin, which on paper looks a very similar drug and one that crosses the blood brain barrier better than Lovastatin.



The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1-/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1-/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX.  

Although we propose the beneficial effect of lovastatin stems from the inhibition of ERK1/2-driven protein synthesis, it is important to note that statins are capable of affecting several biochemical pathways. Beyond the canonical impact on cholesterol biosynthesis, statins also decrease isoprenoid intermediates including farnesyl and geranylgeranyl pyrophosphates that regulate membrane association for many proteins including the small GTPases Ras, Rho and Rac [18, 46, 48, 49]. The increase in protein synthesis seen with simvastatin could be linked to altered posttranslational modification of these or other proteins. Indeed, although we see no change in mTORC1-p70S6K signaling, other studies have shown an activation of the PI3 kinase pathway that could be contributing to this effect [32]. However, our comparison of lovastatin and simvastatin shows that there is a clear difference in the correction of pathology in the Fmr1-/y model, suggesting that the impact on ERK1/2 is an important factor in terms of pharmacological treatment for FX.  There are many reasons why statins would be an attractive option for treating neurodevelopmental disorders such as FX. They are widely prescribed worldwide for the treatment of hypercholesterolemia and coronary heart disease [50], and safely used for longterm treatment in children and adults [46]. However, our study suggests that care should be taken when considering which statin should be trialed for the treatment of FX and other disorders of excess Ras. Although the effect of different statins on cholesterol synthesis has been well documented, the differential impact on Ras-ERK1/2 signaling is not well established. We show here that, contrary to lovastatin, simvastatin fails to inhibit the RasERK1/2 pathway in the Fmr1-/y hippocampus, exacerbates the already elevated protein synthesis phenotype, and does not correct the AGS phenotype. These results are significant for considering future clinical trials with lovastatin or simvastatin for FX or other disorders of excess Ras. Indeed, clinical trials using simvastatin for the treatment of NF1 have shown little promise, while trials with lovastatin show an improvement in cognitive deficits [28-30]. We suggest that simvastatin could be similarly ineffective in FX and may not be a suitable substitute for lovastatin in further clinical trials.


Conclusion
If you are treating Fragile X, best to start with Lovastatin and see if it helps.  In theory it might also help NF1 (Neurofibromatosis Type 1).

It looks to me that Atorvastatin also inhibits the relevant pathway and does much more besides that (PTEN, BCL2 etc)

What is Roche doing with FRAX486?




Thursday 17 May 2018

Statins, SLOS and Hypocholesteraemia – Going Nowhere Fast


Today’s post is about cholesterol, statins and autism. There is a well-documented condition associated with autism called SLOS (Smith-Lemli-Opitz Syndrome). It is caused by mutations in the DHCR7 gene encoding the enzyme that catalyzes the final step in cholesterol biosynthesis.

Toe syndactyly (webbed toes), one symptom of SLOS



Reduced activity of the enzyme 7DHCR typically leads to low levels of cholesterol, but markedly increased levels of precursor 7DHC (and its isomer, 8DHC) in blood and tissues. Typical SLOS manifestations include intellectual disability, growth retardation, minor craniofacial anomalies, microcephaly and 2-3 toe syndactyly (webbed toes).
SLOS is rare, but some cases do get missed because you can have a DHCR7 mutation and have normal levels of cholesterol and have normal cognitive function.

Cholesterol and the blood brain barrier (BBB)
You do have a lot of cholesterol in your brain, but it does not cross the blood brain barrier (BBB), it was made in the brain.  Eating more cholesterol can have no direct effect on cholesterol levels in the brain.
The standard treatment for SLOS has long been oral cholesterol supplementation, but there is no conclusive research to show it helps. There is plenty of anecdotal evidence.

Simvastatin and SLOS
Simvastatin is a drug widely used drug to treat people with elevated cholesterol.
There has been anecdotal evidence that Simvastatin improves SLOS and recently a very thorough study was carried out to establish whether or not it really has a benefit.
In reality the study was comparing:

Simvastatin + cholesterol supplement  vs  cholesterol supplement

The study was carried out by researchers including Dr Richard Kelley (“Dr Mitochondria”) and Dr Elaine Tierney (“Dr Cholesterol”)


Currently, most SLOS patients are treated with dietary cholesterol supplementation. Although cholesterol therapy reduces serum 7-DHC concentrations to a degree, significant amounts of 7-DHC persist even after years of therapy.  Anecdotal case studies and case series support the idea that cholesterol supplementation benefits the overall well-being of SLOS patients; however, the effects of dietary cholesterol supplementation on cognitive or behavioral aspects of this disorder have not been reported by others or substantiated in a limited controlled trial. The efficacy of dietary cholesterol supplementation is probably limited by the inability of dietary cholesterol to cross the blood–brain barrier. Moreover, increased concentrations of 7-DHC or 7-DHC-derived oxysterol could have toxic effects. Specialists have hypothesized that, in patients with mild to classic SLOS, many aspects of the abnormal behavioral and cognitive phenotype could be the result of altered sterol composition in the central nervous system. Thus, interventions that ameliorate the central nervous system biochemical disturbances in SLOS are critical to understanding the pathological processes that underlie this inborn error of cholesterol synthesis and to developing effective therapies to treat the neurological deficits.

Expression of DHCR7 is regulated by SREBP2, which, when activated by low levels of cholesterol in the endoplasmic reticulum, increases the transcription of most genes of the cholesterol synthetic pathway. Having shown that DHCR7 expression is increased in SLOS fibroblasts treated with simvastatin,31 we hypothesized that the paradoxical increase in serum cholesterol could be the result of increased expression of a DHCR7 allele with residual enzymatic function, and we demonstrated that many DHCR7 alleles encode an enzyme with residual activity. Furthermore, both in vitro experiments with human  fibroblasts and in vivo experiments using hypomorphic Dhcr7T93M/delta mice support the hypothesis that increased expression of DHCR7 alleles with residual enzymatic activity can significantly improve plasma and tissue sterol concentrations. Because residual DHCR7 activity varies among patients with SLOS, this hypothesis could explain the paradoxical increase in cholesterol in some patients and the adverse reactions observed in others.

In this study we also evaluated the potential of simvastatin to alter specific aspects of the SLOS behavioral phenotype. Our secondary outcome measures were the CGI-I and ABC-C irritability scores. Although we observed no significant effect on the CGI-I, we did observe significant improvement in the ABC-C irritability score (Figure 4). This article therefore represents the first controlled study to demonstrate improved behavior in subjects with SLOS in response to a therapeutic intervention.




In summary, this study represents the first controlled trial of simvastatin therapy in SLOS and the first controlled trial demonstrating the potential of drug therapy to modulate sterol composition and to improve behavior in SLOS. We have established that treatment with simvastatin is relatively safe, can decrease DHC levels, and can improve at least one aspect of the behavioral phenotype. These data support continued efforts to identify and rigorously evaluate potential therapies that may have clinically meaningful benefits for patients with SLOS.










Plasma sterol levels

Cholesterol and dehydrocholesterol (7DHC + 8DHC) levels were measured at baseline (B), washout (W, 14 mo) as well as at 1, 3, 6, 9 and 12 months in both the placebo and simvastatin treatment phase. Plasma cholesterol levels (A, B) and DHC (C, D) decreased significantly during the simvastatin phase compared to the placebo phase. The plasma DHC/Total Sterol ratio (E, F), which was the primary outcome measure of this study, also decreased significantly. Data expressed as mean ± SEM.


Hypocholesterolemia (low cholesterol) and some Autism
Ten years ago, Tierney and Kelley published research showing that about 20% of autism is associated with very low cholesterol levels (less than the 5th centile for typical young people) but in their sample of 100, none had an abnormally increased level of 7DHC consistent with the diagnosis of SLOS or abnormal level of any other sterol precursor of cholesterol.


Tierney went on to patent cholesterol as a therapy for autism.


The present invention relates to the field of autism. More specifically, the present invention provides methods for treating individuals with autism spectrum disorder. Accordingly, in one aspect, the present invention provides methods for treating patients with autism spectrum disorder. In one embodiment, a method for treating an autism spectrum disorder (ASD) in a patient comprises the step of administering a therapeutically effective amount of cholesterol to the patient. In more specific embodiments, the ASD is autism, Asperger's disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), Rett's syndrome and childhood disintegrative disorder. In one embodiment, the patient has autism. 


Tierney has a clinical trial registered that was to start in 2009.


Three sites (Kennedy Krieger Institute [KKI], Ohio State University [OSU], and the National Institutes of Health [NIH]) will collaborate to accomplish the objectives of this study. In addition to defining the frequency of altered cholesterol homeostasis in ASD, 60 youths (20 at each site) with ASD plus hypocholesterolemia will enter a 12-week, double-blind, placebo-controlled trial immediately followed by a 12-week open-label cholesterol trial to test the efficacy of dietary cholesterol supplementation. Outcome measures will include standard tests of behavior, communication, and other autism features.


It appears that the study has not been completed.


Dr. Elaine Tierney and her colleagues are studying different metabolic disorders that can present with autism spectrum disorder through the Autism Metabolic Research Program at Kennedy Krieger. In 2000 and 2001, this group of researchers identified that Smith-Lemli-Opitz-Syndrome (SLOS) is associated with autism spectrum disorder. Since SLOS is known to be caused by a defect in the body's biosynthesis of cholesterol, SLOS may provide clues to the biochemistry of other autism spectrum disorders (ASD).

Dr. Tierney and colleagues published a paper in 2006, in the American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), in which they describe finding that a subgroup of children with ASD have abnormally low cholesterol levels. The children's low cholesterol levels were apparently due to a limited ability to make cholesterol. This finding, in concert with their work with SLOS, has led them to believe that cholesterol may play a role in the cause of some cases of autism spectrum disorder. Dr. Tierney and colleagues at Kennedy Krieger, the National Institutes of Health and Ohio State University are performing a double-blind placebo-controlled study of cholesterol in individuals with ASD.

Cholesterol as a marker of inflammation
Nowadays, hypercholesterolemia and inflammation are considered as “partners in crime”.  Statins do lower bad cholesterol, but they also have broad anti-inflammatory effects.


Arteries do clog up with cholesterol, but a big part of why this happens is inflammation. Cholesterol deposits are initially a protective mechanism, like a band-aid. Treat the inflammation and cholesterol will not need to be deposited.
An altered immune response is a feature of many people’s autism, and you can measure it.
As Paul Ashwood’s research has shown, there are different immune sub-groups that people with autism fall into, and so you could treat each cluster with a specific therapy.

Cholesterol and Thyroid Hormones
Your thyroid produces hormones that control your metabolism. Metabolism is the process your body uses to convert food and oxygen into energy.

Your body converts the circulating pro-hormone T4 into the active hormone T3 locally. So, in your brain T4 has to be converted to T3. If you lack enough T4 coming from your thyroid gland or the special enzyme called D2 you are going to feel lethargic.
Your body needs thyroid hormones to make cholesterol and to get rid of the cholesterol it doesn’t need. When thyroid hormone levels are low (hypothyroidism), your body doesn’t break down and remove LDL (“bad”) cholesterol as efficiently as usual. Elevated LDL cholesterol will show up in your blood tests.
Hyperthyroidism has the opposite effect on cholesterol. It causes cholesterol levels to drop to abnormally low levels.
So best to check thyroid function and cholesterol levels.



Conclusion
My main interest is autism with a tendency to big heads (hyperactive growth signalling pathways) and an overactive immune system. This is the opposite of SLOS and hypocholesterolemia (low cholesterol).
For the 20% with low cholesterol, I think this is a very important biomarker.

.Is supplemental cholesterol the answer? I am not so sure it is.
Hopefully one day soon Dr Tierney, at Kennedy Krieger, will publish her results of cholesterol as a therapy for people with autism and low cholesterol.
For me it is good to see that Simvastatin was well tolerated in a 12 month long trial in children from 4 to 18 years of age. I have the very similar drug, Atorvastatin, in my Polypill.
Interestingly, in a paper that I will cover in later post, increasing HDL (good cholesterol), a feature of Atorvastatin and Simvastatin, was one marker of behavioral improvement in the Ketogenic Diet.