More Support for the use of Statins in some Autism

Monty, aged 12 with ASD, has been taking Atorvastatin for two years, with a clear cognitive improvement from day one.  

This improvement is lost when this therapy is interrupted.

There are several posts in this blog giving the scientific basis why statins might be beneficial in some autism, these included the genes/proteins RAS, PTEN and BCL2.  In addition, statins possess potent anti-inflammatory properties.

Following a flood of visits to this blog to read about statins and autism, I did a quick check and in recent weeks at least three papers have been published suggesting the potential for statins to improve some autism.

I include the word “some” because with 800 currently identified autism genes, and I expect eventually it will be thousands, what works for one person’s “autism” may not help the next person’s “autism” and might even make it worse.

The first paper is the one getting the media coverage, it is from the University of Edinburgh, plus Mark Bear et al from MIT.  Mark Bear’s lab has featured in this blog several times, particularly relating to Fragile-X.  Lovastatin is being already trialed in humans with Fragile-X.

I use Atorvastatin (Lipitor) because it has best side effect profile.  Lovastatin and Simvastatin will have the same effect.  In some countries these drugs are available cheaply OTC.

Their therapeutic effect in autism, based on my sample of one, is from the first pill.

Over to the "experts":-

Cholesterol drug could aid autism sufferers

Intellectual disabilities and autism spectrum disorders could share similar defects although their genetic causes are different, according to Scottish scientists.

A study of two models of intellectual disability in mice by Edinburgh University has found that they share similar disease mechanisms.

Researchers also found that treatment with a statin drug called Lovastatin, which is often used to treat high cholesterol, can correct high levels of protein production in the brain linked to the conditions.

The findings suggest that different types of intellectual disabilities may benefit from common therapeutic approaches, the researchers say.

Professor Peter Kind, Director of the University of Edinburgh’s Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities, said: “Statins, such as lovastatin, are already used widely for treating people, including children, for high cholesterol with minimal side effects.

“Further studies are needed to determine whether these existing medications could also help people with intellectual disabilities.”

The study has been published in the Journal of Neuroscience

The full paper is here:-

Convergence of Hippocampal Pathophysiology in Syngap+/− and Fmr1−/y Mice

Abstract

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap^+/− and Fmr1^−/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap^+/− hippocampal slices. Super-resolution microscopy reveals that Syngap^+/− and Fmr1^−/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras–ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.

SIGNIFICANCE STATEMENT As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap^+/− mice phenocopy Fmr1^−/y mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu₅ receptor–ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1^−/y mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.

The other two papers are from 2015 Society for Neuroscience annual meeting in Chicago.

  

Experimental cancer drug eases autism symptoms in mice

A drug that blocks a cancer-related pathway normalizes neuron number and prevents behavior problems in mice that lack a copy of the autism-linked chromosomal region 16p11.2. Researchers presented the unpublished results yesterday at the 2015 Society for Neuroscience annual meeting in Chicago.

Loss of 16p11.2 results in intellectual disability, enlarged head, obesity and, often, autism. This region spans 27 genes — including one called ERK1, part of a signaling cascade that regulates cell growth. The cascade, called the RAS pathway, is hyperactive in some types of cancer and in four rare autism-linked neurodevelopmental disorders, collectively dubbed ‘RASopathies.’ The proteins encoded by ERK1 and the related ERK2 gene carry out many of the molecular consequences of RAS pathway activation.

Paradoxically, the ERK proteins are hyperactive in mice lacking a copy of 16p11.2¹. This hyperactivation coincides with a period of intense neuron development in the mouse embryo. The animals also have too few neurons in some parts of the cerebral cortex, the brain’s outer layer, and too many neurons in others.

“Because of this aberrant ERK hyperactivity, we were thinking that we can potentially try to bring the levels down by using a specific ERK inhibitor,” says Joanna Pucilowska, a postdoctoral fellow in Gary Landreth’s lab at Case Western Reserve University in Cleveland, Ohio.

Sniffing clues:

Pucilowska and her colleagues used an experimental drug that blocks activation of the ERK proteins. They injected the drug into pregnant mice to investigate its effects on neuron development in mouse embryos.

Treating mice with the drug prenatally for five days stabilizes ERK activity, the researchers found. It also normalizes neuron numbers in the cerebral cortex.

The treatment has lasting effects on behavior, too. Unlike untreated mice that lack a copy of 16p11.2 — which are underweight, hyperactive and have memory problems — the treated mice resemble those that do not have the chromosomal deletion.

The researchers discovered for the first time that mice lacking 16p11.2 are quicker than those without the deletion to sniff out a hidden snack in their cage, suggesting they have a highly acute sense of smell, like some people missing 16p11.2. Female mice with the deletion are also faster to retrieve pups that stray from the safety of their nest, an innate maternal behavior. The drug treatment normalizes both behaviors.

Pucilowska says she and her colleagues would like to test the drug in cells derived from people missing a copy of 16p11.2. If it works in human cells the same way it does in mice, then it might be possible to treat people with the deletion using cholesterol-lowering drugs called statins, which are also known to block signaling in the RAS pathway. “This can potentially lead to the first treatment for children with 16p11.2 deletion,” Pucilowska says.

Autism model reveals brain processes behind ‘super’ skills

Structural changes in the connections between neurons may underlie the enhanced learning and motor skills seen in mice with an extra copy of the autism-linked gene MeCP2. Blocking these changes with a drug blunts the animals’ performance.

The findings, presented yesterday at the 2015 Society for Neuroscience annual meeting in Chicago, point to neural mechanisms underlying the restricted interests and, in some cases, exceptional learning abilities seen in people with autism.

“This could lead to enhanced learning and enhanced performance in constrained behaviors, like in autistic savants,” says Ryan Ash, a graduate student in Stelios Smirnakis’ lab at Baylor College of Medicine in Houston. “Maybe they can’t iteratively refine those kinds of behaviors over time, so they get stuck in a behavior, which can be exceptional in certain cases but then impaired in others.”

People carrying an extra copy of MeCP2 often have autism. Mice with the same duplication have autism-like symptoms, such as avoiding social interactions with other mice.

“But they also have a super-learner phenotype,” Ash says. They perform better than controls do on a test of motor skill learning that involves balancing on a rotating rod. Typical mice fall off the rod as its speed increases, but mice with the duplication learn to coordinate their feet so that they can stay on about 30 seconds longer.

When mice learn a motor task, new synapses, connections between neurons, form in the brain¹. The researchers suspected that the superior learning abilities of the mice carrying the extra MeCP2 might stem from alterations in the formation and stability of these neuronal links.

To test this hypothesis, the researchers used microscopy to image neurons in the brain that connect to the spinal cord and control movement. They took pictures of the same neurons before and after the mice practiced the rotating rod test for four days, and again after the animals had four days of rest.

Spine support:

As expected, training spurred neurons in typical mice to form new signal-receiving projections, called dendritic spines. About half of these spines remained after four days of rest, suggesting the formation of stable memories. Mutant mice form more spines than controls do, and more of them stay put after the mice take a break.

The stable spines tend to cluster. Enhanced performance on the rod tracks with a greater number of clustered spines remaining after the rest period.

“We think this is important because spines that are near each other can drive the cell more strongly when they get activated at the same time,” Ash says.

Training stimulates greater activation of a signaling cascade called the RAS pathway in the mutant mice than it does in controls. Activation of this pathway is known to strengthen clustered spines².

Blocking the activation of this pathway with an experimental drug called SL327 lowers the mutants’ performance on the rotating rod back to the normal range. And the spines in these animals also look more like those of typical mice.

The findings suggest that spine formation and stability underlie the enhanced learning abilities of the mutant mice. Both processes appear to depend on the activation of the RAS pathway.

The drug the researchers used lasts only for a few hours, so it is not likely to help people with autism, Ash says. But cholesterol-lowering drugs called statins block activation of the same pathway by a different mechanism. “Maybe you could do a more chronic treatment with a statin, but we haven’t tried that yet,” he says.

Other mouse models of autism show enhanced performance on the rotating rod test. These include mice with a duplication in chromosomal region 15q11-13 and with mutations in the CNTNAP2, NLGN3 and NRXN1 genes, Ash says.

Interestingly, mice that lack a copy of MeCP2 — the gene mutated in the autism-linked disorder Rett syndrome — have impaired performance on the same test, and show reduced spine stability. “I would hypothesize that all of these things are actually the opposite in the Rett mice,” Ash says.

The Brain is Hypothermic in Mitochondrial Disease, but is it in Autism?

Having noted in the previous post something as simple, and measurable, as reduced blood flow in the brain exists in autism, I decided to dig a little deeper.

Not only can you measure blood flow in specific regions of the brain, but using Magnetic Resonance Spectroscopy you can measure the temperature of the brain.

Intense heat production is an essential feature of normal brain energetics; most of the energy used for brain functioning is eventually released as heat.  In the brain, heat is produced mostly by mitochondrial oxidative chemical reactions. Most of the energy required for brain activity is generated from the net chemical reaction of oxygen and glucose; some of this energy (33%) is immediately dissipated into heat, and the rest (67%) is used to synthesize ATP. The final ATP hydrolysis releases part of the energy back to the system as heat.

Note that your core temperature is not the same as your brain temperature.

Brain temperature T_br should be near constant

Increases in Cerebral Blood Flow reduce T_br and increases in brain metabolism increase T_br.

Neuronal activity is temperature dependent, with neuronal firing increasing with increased temperature.  Many other functions in the brain are temperature dependent.

When your brain gets too hot febrile seizures can be the result, caused by excessive neuronal firing.

Mitochondrial Disease

Since heat in the brain is produced mostly by mitochondrial oxidative chemical reactions, when mitochondrial disease is present, it would be expected that there would be less heat and therefore a lower Brain temperature T_br.  This time biology is indeed logical and this is the case.  People with mitochondrial disease have measurably colder brains.

The brain is hypothermic in patients with mitochondrial diseases

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.

The question is whether this lower brain temperature, in itself, leads to changes in brain function/performance and hence mood, behaviours and cognition.

Mitochondrial Disease in Autism

There are various types of mitochondrial disorder in autism and, confusingly, different terminology is used for similar biological conditions.  Regressive autism triggered by a viral illness, fever, or in some cases a reaction to a vaccine is likely mitochondria-related.

I have covered Dr Kelley from Johns Hopkins ideas on this subject, but there are others.  Here are some other perspectives:-

Has Your Child with Autistic Symptoms Been Properly Screened for a Subset of  Mitochondrial Disease Known as OXPHOS?

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

Fever Effect in Autism

It is well documented that in many people with autism their symptoms subside when they are sick and have a fever.  This is the so-called “fever effect”.  It only applies to some people with autism and in a small number the effect can be dramatic.

There are numerous unproven theories.

A Study of Behaviors Associated with Fever in Children with Autism/PDD

Hyperthermia and the amelioration of autism symptoms 

  

Hyperthermia and the Improvement of Autism Spectrum Disorder (ASD) Symptoms

Background:  The observation that some ASD patients manifest clinical improvement in response to fever suggests that symptoms may be modulated by immune-inflammatory factors.  The febrile hypothesis of ASD stems from this observation, and could be due to (1) the direct effect of temperature; (2) a resulting change in the immune inflammatory system function associated with the infection of fever; and/or (3) an increase in the functionality of a previously dysfunctional locus coeruleus-noradrenergic (LC-NA) system.  

Objectives:  To assess the effect of hyperthermia on ASD symptoms.

Methods:  We completed a double blind crossover study of 15 children with ASD (5 to 17 years) using two treatment conditions, hyperthermia condition (102°F) and control condition (98°F) in a HydroWorx aquatic therapy pool.  Five children with ASD without fever response acted as controls, completing only the hyperthermia condition, to ensure safety and feasibility.  Safety measures and Social Responsiveness Scale (SRS) were collected.  Ten patients with ASD and history of fever response were enrolled and received both treatment conditions.  Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool.  Parents completed the SRS and RBS-R.  Pupillometry biomarker and buccal swabs for DNA and RNA extraction were collected pre and post pool entry. 

Results:  Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102°F) and control condition (98°F) at the aquatic therapy pool.  Improvement during the hyperthermia condition (102°F) was observed in social cognition, using the Social Responsiveness Scale (SRS) total raw score (p = 0.0430) and the SRS Social Behavior subscale raw scores (p = 0.0750); repetitive behaviors, using the Repetitive Behavior Scale-Revised (RBS; p =0.0603) and the SRS Restricted and Repetitive Behavior subscale (p = 0.0146); and on global improvement, using the Clinical Global Impression Scale-Improvement (CGI-I; p=0.0070). 

Conclusions:  This study demonstrates the feasibility of observing the direct effect of temperature in children with ASD, both with and without a history of febrile response, and provides preliminary data on the relationship between body temperature and changes in social and behavioral measures. It explores the direct effects of temperature on ASD symptoms, and offers a window into understanding mechanisms involved in improvement in ASD symptoms during fever episodes.  Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. This study is important for the development of translational models on the mechanism of symptom improvement and the identification of novel targets for therapeutic development.

Why not measure Brain temperature T_br in a large number of people with Autism?

The above study at the “Albert Einstein” medical school involved putting people in hot tubs to warm them up and then measuring their autistic symptoms. You would have thought it would have occurred to them to quickly pop upstairs to the MRI to measure brain temperature T_br.  I do not think you need to be an Einstein to think of that.

Perhaps the people that exhibit the fever effect are the ones with low brain temperature T_br ?  That would seem well worth checking.

It also is logical to just warm up the part of the body that will affect behaviour.

Hypothermia in Mouse Models

If you look up hypothermia and autism you again encounter Robert Naviaux, from University of California San Diego, and not much else.  Naviaux is a very clever researcher, but more importantly he just does not give up.  He is doggedly pursuing his antipurinergic therapy for autism.

It turns out that hypothermia is a feature of the maternal immune activation (MIA) mouse model of autism that he is using in his research.

Indeed his antipurinergic therapy corrects this hypothermia.

From:-

Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.

Relative hypothermia is a long-term feature of the Poly(IC) MIA Model. This is the lower line (PICSAL), when treated with Suramin, you get the yellow line PICSUR, with a higher body temperature similar to that of the regular mice (blue lines)  When they gave Suramin to regular mice (dark blue line) the was no overall change in body temperature.

So we know that in at least one major mouse model of autism, hypothermia is known feature.  Did anyone measure it in the others?

Conclusion

If raising T_br improves autism symptoms so much, in some people, then why not just figure out a clever way to increase it?

Raising blood flow apparently should lower T_br.

There are likely numerous options like increasing the oxygen level in the blood, which might be expected to increase heat production, for example using Diamox (Acetazolamid). 

Reducing heat loss by wearing a wooly hat, should marginally raise brain temperature, unless the brain then compensates for this.

Since the illicit drug MDMA, or ecstasy, is already known to raise brain temperature, there probably are ways to develop a safe drug therapy to achieve a small increase in brain temperature.  

  

Hopefully Naviaux will find a safe antipurinergic therapy, which might also be used in people with low T_br, as well as broader autism.

Brain Hypoperfusion in Autism & Cocoa

Today’s post is simpler than many earlier ones and is actionable.

A known feature of many neurological conditions like Alzheimer’s and dementia is reduced blood flow to certain parts of the brain.  In the medical jargon this is called hypoperfusion.

This reduced blood flow is also present in autism and is measurable by MRI.

We encountered epicatechin in early posts on cocoa flavanols.  It would seem that one of epicatechin’s many effects is to increase cerebral blood flow. 

Two chocolate companies, Mars (Cocoavia) in the US and Barry Callebaut (ACTICOA) in France, have developed high flavanol cocoa.  10 g of their cocoa contains about 1 g of flavanols and produces cognitive benefits; even a quarter of this dose gives the cardiovascular benefits.  Mars, in particular, are funding a great deal of research and have committed to a five year project with Harvard.  The high flavanol products are available today.

Brain Perfusion Anomalies in Autism

While most research focuses on Alzheimer’s and other types of cognitive impairment and memory loss, there are studies on brain perfusion in autism.

Cerebral perfusion abnormalities in children with autism and mental retardation: a segmental quantitative SPECT study.

  

Autism is a severe developmental disorder, the biological mechanisms of which remain unknown. Hence we conducted this study to assess the cerebral perfusion in 10 children with autism and mental retardation. Five age matched normal children served as controls. These cases were evaluated by single photon emission computed tomography (SPECT) using Tc-99m HMPAO, followed by segmental quantitative evaluation. Generalized hypoperfusion of brain was observed in all 10 cases as compared to controls. Frontal and prefrontal regions revealed maximum hypoperfusion. Subcortical areas also indicated hypoperfusion. We conclude that children with autism have varying levels of perfusion abnormities in brain causing neurophysiologic dysfunction that presents with cognitive and neuropsychological defects.

  

Significant hypoperfusion was observed at cortical and subcortical areas of brain in autistic subjects, suggesting that the structural abnormalities

of these brain areas may result in reduced cortical activity, thus causing dysfunction of these brain areas, and eventually producing some of the

emotional and behavioral disorders usually described in autistic subjects. These SPECT findings may help to explain several behavioral features of autism, such as impulsive and aggressive behaviours (to self and others), motor disinhibition (such as stereotypic and manneristic movements and echophenomena), and deficits in planning, sequencing and attention.

Abnormal regional cerebral blood flow in childhood autism

Neuroimaging studies of autism have shown abnormalities in the limbic system and cerebellar circuits and additional sites. These findings are not, however, specific or consistent enough to build up a coherent theory of the origin and nature of the brain abnormality in autistic patients. Twenty-three children with infantile autism and 26 non-autistic controls matched for IQ and age were examined using brain-perfusion single photon emission computed tomography with technetium-99m ethyl cysteinate dimer. In autistic subjects, we assessed the relationship between regional cerebral blood flow (rCBF) and symptom profiles. Images were anatomically normalized, and voxel-by-voxel analyses were performed. Decreases in rCBF in autistic patients compared with the control group were identified in the bilateral insula, superior temporal gyri and left prefrontal cortices. Analysis of the correlations between syndrome scores and rCBF revealed that each syndrome was associated with a specific pattern of perfusion in the limbic system and the medial prefrontal cortex. The results confirmed the associations of (i) impairments in communication and social interaction that are thought to be related to deficits in the theory of mind (ToM) with altered perfusion in the medial prefrontal cortex and anterior cingulate gyrus, and (ii) the obsessive desire for sameness with altered perfusion in the right medial temporal lobe. The perfusion abnormalities seem to be related to the cognitive dysfunction observed in autism, such as deficits in ToM, abnormal responses to sensory stimuli, and the obsessive desire for sameness. The perfusion patterns suggest possible locations of abnormalities of brain function underlying abnormal behaviour patterns in autistic individuals.

Cerebral Hypoperfusion and HBOT?

One therapy proposed to treat Cerebral Hypoperfusion in autism is hyperbaric oxygen therapy (HBOT).  Some proponents go as far as to link specific areas of the brain to specific autistic features as below.

The mainstream view, among those using HBOT for other conditions, is that it would not help stimulate increased blood flow in autistic brains.  But there are proponents of the therapy like Rossignol.

Hyperbaric oxygen therapy may improve symptoms in autistic children

You may have realized that the science exists to test, once and for all, whether HBOT can improve cerebral blood flow in autism.  It just takes two visits to an MRI.

Perfusion MRI Lab: How can we measure cerebral blood supply

I did see a report about a US neurologist who showed via MRI that the cerebral blood flow of his autistic patient improved using HBOT and he tried to use this to get access to the further HBOT on insurance.

Hypoperfusion in Alzheimer’s, Dementia  and Cognitive Impairment

Reduced cerebral blood flow is a marker of incipient dementia.  I expect one day this might even be used to trigger preventative therapy.

Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study.

Abstract

Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimer's disease. It is being debated whether this reflects diminished demand because of advanced neurodegeneration or that cerebral hypoperfusion contributes to dementia. We examined the relation of CBF velocity as measured with transcranial Doppler with dementia and markers of incipient dementia (ie, cognitive decline and hippocampal and amygdalar atrophy on magnetic resonance imaging) in 1,730 participants of the Rotterdam Study aged 55 years and older. Cognitive decline in the 6.5 years preceding CBF velocity measurement was assessed with repeated Mini-Mental State Examinations in nondemented subjects (n = 1,716). Hippocampal and amygdalar volumes were assessed in a subset of 170 nondemented subjects. Subjects with greater CBF velocity were less likely to have dementia. Furthermore, in nondemented subjects, greater CBF velocity was related to significantly less cognitive decline over the preceding period (odds ratio per standard deviation increase in mean CBF 0.74 [95% confidence interval, 0.58-0.98]) and larger hippocampal and amygdalar volumes. A low CBF is associated with dementia, but also with markers of incipient dementia. Although we cannot exclude that this is caused by preclinical neurodegeneration leading to hypoperfusion, it does suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia.

Vascular dementia

Vascular dementia is the second-most-common form of dementia after Alzheimer's disease.  It is a much simpler condition, it is dementia caused by problems in the supply of blood to the brain, typically by a series of minor strokes.

The incidence peaks between the fourth and the seventh decades of life and 80% will have a history of hypertension. Patients develop progressive cognitive, motor and behavioural signs and symptoms.

Blood pressure rises with aging and the risk of becoming hypertensive in later life is considerable

It would seem that you could treat hypertension and vascular dementia with the same preventative therapy.  See the clinical trial on treating vascular aging with Cocoa, later in this post.

It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension. 

In essence you want to control peripheral resistance and before it is too late.  It really is a case of “a stitch in time saves nine”.

The research done in to peripheral resistance / vascular stiffness can be re-purposed to help us treat brain hypoperfusion.  In autism we may have Brain Hypoperfusion, but without high blood pressure (hypertension).

Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial

Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (<35 years) and 20 elderly (50–80 year) healthy, male non-smokers consumed either a CF-containing drink (450 mg CF) or nutrientmatched, CF-free control drink bi-daily for 14 days.

The primary endpoint was endothelial function as measured by flow-mediated vasodilation (FMD). Secondary endpoints included cardiac output, vascular

stiffness, conductance of conduit and resistance arteries, and perfusion in the microcirculation. Following 2 weeks of CF intake, FMD improved in young (6.1±0.7 vs. 7.6±0.7 %, p<0.001) and elderly (4.9 ± 0.6 vs. 6.3 ± 0.9 %, p < 0.001).

Secondary outcomes demonstrated in both groups that CF intake decreased pulse wave velocity and lowered total peripheral resistance, and increased arteriolar and microvascular vasodilator capacity, red cell deformability, and diastolic blood pressure, while cardiac output remained affected. In the elderly, baseline systolic blood pressure was elevated, driven by an arterial-stiffness-related augmentation.

CF intake decreased aortic augmentation index (−9 %) and thus systolic blood pressure (−7 mmHg;

Cocoa Flavanols

I did write an earlier post about the various benefits of Cocoa Flavanols. 

Why not Cocoa Flavanols for Autism?

  

Here is a very good review paper:-

The neuroprotective  benefits of cocoa flavanol and its influence on cognitive performance

Norman Hollenberg, at Harvard, has been an advocate of high flavanol cocoa for decades.  Here is one of his papers.

Cocoa and Cardiovascular Health

Using functional MRI, the following study measures the effect on brain blood flow, before and after taking a high flavanol cooca drink

Cocoa Flavanols and fMRI showing effect on Brain Perfusion

The effect of flavanol-rich cocoaon cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial

There is now good evidence that the acute benefits for cognitive function and blood flow exerted by cocoa flavanol consumption peak approximately 90–120 min postconsumption (Schroeter et al. 2006; Francis et al. 2006; Scholey et al. 2010; Field et al. 2011); however, it is presently unclear whether separate chronic mechanisms exists following cumulative consumption over several weeks and months, or indeed whether chronic consumption enhances the effectiveness of acute mechanisms in a cumulative fashion. Despite several plausible mechanisms for increased neuronal activity (as described above), it remains to be seen whether a single cocoa flavanol dose-induced increase in CBF is associated with concomitant benefits in cognitive performance in the immediate postprandial period. More broadly, recent reviews of acute interventions and epidemiological surveys provide good evidence that flavonoids and their subclasses are beneficial for cognitive function

In conclusion, the present findings support the hypothesis that flavanol-rich cocoa beverages are associated with increased CBF within a 2-h post-prandial time frame. More specifically, increased brain perfusion following the HF drink relative to the LF drink was observed in the anterior cingulate cortex and a region in the left parietal lobe. These data add to the substantial body of literature demonstrating that flavanol consumption is beneficial for peripheral and cerebral vascular function and thus for maintaining, protecting and enhancing cardiovascular health.

Does High Flavanol Cocoa have an effect in Autism?

This is probably the question you have been asking yourself.

I did acquire some ACTICOA, high flavanol cocoa some time ago.  I was wondering how I was going to administer enough of it to make a trial.  In the trials on improving memory in older adults 10g a day was needed.

While adding it to milk seems an obvious choice, Hollenberg suggests that the milk may neutralize the flavanols.  This is true with black tea; once you add milk you lose its healthy antioxidant properties.

In the end I choose to add 5ml to the breakfast broccoli powder and water concoction and mix with a frappe mixer.  Monty, aged 12 with ASD, was the ever willing test subject.

Two and a half hours later there was unprompted laughter and smiling.  This is repeated each time I give the ACTICOA  cocoa.

According to the literature, the peak level of epicatechin occurs 2 to 3 hours after consuming cocoa.

Then I tried a regular raw cocoa powder at the same dose; no laughter.

So I conclude that ACTICOA is indeed different to regular non-alkalized cocoa powder.  The more common alkalized cocoa has virtually no flavanols at all, and this is what is used to make most chocolate and is sold in supermarkets as "cocoa".

There are potentially other sources of epicatechin, but you really want a reliable standardized product.  If you live in the US/Canada this is easy; you can buy the Cocoavia product from Mars.  It is not cheap if you want 1g of flavanols a day.

The literature does suggest that there is a cumulative effect of taking epicatechin and Hollenberg has documented that regular consumption of unprocessed cocoa (rich in flavanols) is associated with numerous health benefits, particularly related to blood flow (strokes, heart attacks, endothelial dysfunction, cholesterol etc.)

Since Mars are now funding considerable research into the health benefits of these flavanols, I did think of suggesting they look at autism.

They could take a group of people with autism, measure their IQ and then score their autism using one of the standard scales.  Then off to the MRI to measure blood flow and velocity in different parts of the brain.

Give half of the test subjects a daily high flavanol drink and the other half a low flavanol drink.  After three months, repeat the IQ test, autism test and measure blood flow again via MRI.

I suspect that reduced blood flow/hypoperfusion would be more present in those with lower IQ and that they might show improved IQ at the end of the trial.  I suspect that in terms of autism, most would show an improvement on the high flavanol treatment.

I would like to think that after three months, blood flow/velocity would have increased.

You could then repeat on people with Down Syndrome and more general MR/ID.