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.

Why not Cocoa Flavanols for Autism?

  

Judging by my blog statistics, lots of people are interested in broccoli (Sulforaphane) to treat autism.  Thanks to the patents held by Johns Hopkins, you can expect to hear much more about Sulforaphane in the coming years.

Meanwhile, Columbia University and Mars, the chocolate people, have released a study showing that “flavanoids” in cocoa can do wonders for memory loss in older people.  In effect, they can restore memory in 60 years olds to where it was 20 or 30 years earlier.

If you take a step back and look at what is known by science about oxidative stress and antioxidants, all will become much clearer.

Oxidative Stress Pioneers

In an earlier post we met Paul Talalay, a German-American, who worked at Johns Hopkins.  He specializes in foods that protect you from cancer.  He is Mr Broccoli. 

It turns out that perhaps the real pioneer in this field is a 100% German, called Helmut Sies, who also studies foods that act as antioxidants and nutrients that provide protection from cancer.  We have his very detailed diagram below, that explains the relationship between many of the factors involved in oxidative stress.  I wish I had found it earlier.  I added the six outer boxes.

If you want to read clever studies about this subject, just include Helmut Sies in your search; for example “selenium Helmut Sies”.

Redox Pioneer: Professor Helmut Sies

On this graphic you will see GSH (Glutathione).  When you take NAC (N-acetylcysteine) you directly raise the level of GSH.  When eat broccoli you activate Nrf2, which is a Redox switch, just under the traffic light in the graphic.

When you eat certain flavonoids, like Cocoa, or carotenoids like lycopene (found in tomatoes), you again promote the anti-oxidative free radical scavenger effect.  Look in the blue boxes under diet.

Not on the diagram, we also have flavonolignans which are natural phenols composed of a part flavonoid and a part lignan. As pointed out in a comment in the last post by Seth Bittker, one interesting  flavonolignan is Silibinin, which has anti-oxidant and chemoprotective effects

Note the presence of (Coenzyme) Q10 in the yellow box.  This is part of the mitochondrial cocktail suggested by Dr Kelley from Johns Hopkins for regressive autism.  Q10 is depleted by statins.

Glutathione peroxidases, in the yellow box, are also very interesting.  These are selenium-containing enzymes.  GPx (x goes from 1 to 8)  catalyze the reduction of H₂O₂ and organic hydroperoxides to harmless products. This function helps to maintain membrane integrity and to reduce further oxidative damage to molecules such as lipids and lipoproteins with the associated increased risk of conditions such as atherosclerosis.  It appears GP₁ may be defective in autism and this is contributes to increased oxidative stress.  This area has been well studied due to its impact on heart disease.  You appear to be able to counter the lack of GPx with yeast-bound selenium, other forms of selenium do not work, due to a lack of bioavailability. A post will appear just on Selenium.

There are several other potent (exogenous) antioxidants that we have come across:-

• Alpha lipoic acid also known as ALA or Tioctic acid (found  in Dr Kelley’s cocktail)
•   L-Carnosine (studied by Dr Chez )
•  Vitamin C (suggested by many, including Dr Kelley)

Another day, another anti-oxidant

In human health, two well used anti-oxidant drugs are Alpha lipoic Acid (ALA,  also known as Tioctic acid) and N-acetyl cysteine (NAC).  They share many similar effects.

•       Potent antioxidant
•       Increase insulin sensitivity
•       Improve memory in those with mild cognitive          impairment
•       May lower blood pressure
•       Improve behavior in autism

NAC is widely used to treat Chronic obstructive pulmonary disease (COPD) and ALA is used to treat diabetic neuropathy. Perhaps they could be interchanged

·        NAC has a chemoprotective effect
·        ALA has been shown to induce cell cycle arrest in  human breast cancers      cells

Back to Cocoa Flavanols and Mars

This flurry of activity was driven by a well publicized study done at Columbia University Medical Center (CUMC), using a high cocoa flavanol concentration drink provided by Mars.

Dietary cocoa flavanols reverse age-related memory decline

   

In the CUMC study, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months. Brain imaging and memory tests were administered to each participant before and after the study. The brain imaging measured blood volume in the dentate gyrus, a measure of metabolism, and the memory test involved a 20-minute pattern-recognition exercise designed to evaluate a type of memory controlled by the dentate gyrus.
The high-flavanol group also performed significantly better on the memory test. “If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old,” said Dr. Small. He cautioned, however, that the findings need to be replicated in a larger study—which he and his team plan to do.

This is very impressive.  But how do the other anti-oxidants compare?

Well, without funding from Mars, researchers only managed the money to test ALA and NAC on mice; but as you might expect, the result was similar.

The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice

Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

Cocoa Flavanols are good for your heart

This is also good news, but it does seem that antioxidants are generally very good for your heart.

First cocoa.

In this study blood pressure, glucose, insulin and cholesterol were all markedly affected for the better by the cocoa as was cognitive function.

This is great;  but it is what Helmut Sies has been telling the world for many years.

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment

The Cocoa, Cognition, and Aging (CoCoA) Study

Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing _990 mg (high flavanols), _520 mg (intermediate flavanols), or _45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P_0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P_0.05) lower in subjects assigned to high flavanols (38.10_10.94 and 104.10_28.73 seconds, respectively) and intermediate flavanols (40.20_11.35 and 115.97_28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60_17.97 and 139.23_43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P_0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50_6.75 versus 22.30_8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained _40% of composite z score variability through the study period (partial r2_0.4013; P_0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

There are more cocoa studies:-

Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults  The effect of acute consumption of a flavonol-rich cocoa drink on cerebral vasomotor reactivity in African Americans

Mars Cocoa Science website

Cocoa Flavanols as a therapy for Autism

Based on the work of Helmut Sies and the trials funded by Mars, it is pretty obvious that 1,000mg of cocoa flavanols a day would very likely have a marked effect on someone with autism, assuming that is they were not already taking NAC, ALA, Carnosine, Broccoli, Sulforaphane or Selenium.  500 mg should also have an effect.

Choice of antioxidant

The question is what is the ultimate treatment for oxidative stress in autism?

I guess this will depend on exactly what type of autism you have (regressive or not), to what extent you have a mitochondrial dysfunction and whether you have any genetic dysfunction related to oxidative stress.

What works best in Billy, may be suboptimal in Charlie, but still much better than nothing at all.

It looks to me that NAC and ALA will likely be the most potent antioxidants.

If you live in the US, you can buy cocoa flavanols in standardized doses from Mars.  One capsule = 125mg of cocoa flavanols.   I have to add that I am far more inclined to believe Mars, than those supplement companies out there.  You can buy tablets saying they contain 50 mcg of Selenium, but what do they really contain? 

You can also buy “high flavanol” raw (non-alkalized) cocoa powder in big bags.  This lighter brown cocoa has lost far less of the flavonoids in the processing process.  In theory, a 5g teaspoon of the very best one will contain (on a good day) 415 mg of flavavols.

Mars are only supplying their CocoaVia products in North America, so if you want to try cocoa flavanols you have a few options:-

·        8.5 teaspoons of standard raw cocoa  (content will vary widely)

                or

·        1.2 teaspoons of “Chococru” upmarket raw cocoa

                or

·        4 capsules of CocoaVia from Mars  

Each of the above should give you 500mg of cocoa flavanols, which would look like a good starting point.  As with NAC, the studies show that the benefit increases the more you take, but the extra benefit drops off.

If somebody in the US tries CocoaVia, do let us know the result.

Not surprising, Mars tell us on the label that the product is not intended for children.  I do not suppose they ever thought of it being an autism therapy either.

I do like the idea of the redox switch, Nrf2, which Sulforaphane is known to activate.  I also like the idea of the enzyme GP₁ that acts as catalyst in the oxidation/reduction process.

The science is around 20 years old and nobody has yet figured it all out;  they probably will not conclusively do so in the next 20 years either.

Food for thought!