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Monday, 2 November 2015

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.



  
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.




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.




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).




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 (5080 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. 


  
Here is a very good review paper:-



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





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









There is now good evidence that the acute benefits for cognitive function and blood flow exerted by cocoa flavanol consumption peak approximately 90120 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.








16 comments:

  1. Peter. I'll probably try this soon, but I would like to get a better understanding of the dosing you used.

    You said you mixed in 5 ml with the broccoli powder. Does 5 ml represent the coco product as a whole, or the flavanols within? I'm guessing you meant 5ml of the product (or grams?) which contains .about 50 gm of flavanols. Also, are you doing it multiple times per day?

    Thanks!

    ReplyDelete
    Replies
    1. One teaspoon is 5.9ml and I think is about 2.5g. So if you use ACTICOA you might need as much as 4 teaspoons a day. This is a lot. The most I used was two teaspoons in one go.
      If you use Cocoavia, you can buy capsules with an exact amount in mg of flavanols.
      In various trials 500mg of flavanols has a good effect, but 1,000mg was better. So i thought I would aim for 500mg which I think will take two teaspoons of ACTICOA.
      In trials they give it once a day, but this may be more for convenience. Looking at the half-life of epicatechin makes me think twice a day should be better. You can drink two teaspoons of cocoa, drinking four would not be pleasant.
      10g of ACTICOA contains 1g of flavanols. For the Mars CocoAvia product they have done the conversion to mg of flavanols for you, just look at their product details on their website.

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  2. So are you taking 500mg once per day, or 250mg twice per day?

    ReplyDelete
    Replies
    1. I am still experimenting and where we live none of these products are available, which complicates matters. I give the broccoli twice a day, but the second dose is a half dose. I think this may also be wise for the cocoa, but it is still early days. If you are doing to trial it, the first thing is see if there is any effect, then you can fine tune the dosage.

      Delete
  3. HI
    great post -- isn't this what some of the benefits of baby aspirin are supposed to do? (recognizing there are side effects, etc)

    Also, aren't there many cases of autism where there is hyperfusion so this would aggravate the problem?

    I am hoping that people who try this -let us know their findings. Thanks, MH

    ReplyDelete
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    1. Within "autism" there are often both extremes, hypo and hyper, so I would not be surprised if there were people with hyperperfusion. The research I found only referred to hypoperfusion. It would be nice to know if this correlates with cognitive ability (IQ), at least some of the time.

      Trials on aspirin have show reduction in cerebral blood flow and the opposite, like the one below:-

      Randomized Clinical Trial of Daily Aspirin Therapy in Multi-Infarct Dementia
      http://onlinelibrary.wiley.com/doi/10.1111/j.1532-5415.1989.tb05688.x/abstract;jsessionid=2113DC07393D92F100DD18E27ABE9BE3.f01t03?userIsAuthenticated=false&deniedAccessCustomisedMessage=

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    2. The aspirin treated group improved-- but was it the perfusion that you are mentioning? I am confused.

      Significant improvements were demonstrated for cerebral perfusion values (P < .0001) and cognitive performance scores (P < .0001) among aspirin-treated patients compared to untreated controls at each of three annual follow-up evaluations. Both men and women benefited from aspirin therapy and their quality of life and independence appeared to be improved, which was not apparent in the control group. Daily aspirin appears to improve or stabilize declines in cerebral perfusion and cognition among patients with multi-infarct dementia.

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    3. The cited study does support the use of aspirin, but there are some other ones that are not as supportive.

      http://stroke.ahajournals.org/content/42/9/2571.long

      These studies are all looking at slightly different things and you really want to know the effect of aspirin in otherwise healthy people, who happen to have autism.

      Given many people with autism have GERD/GORD/reflux and other GI problems, long term use of aspirin might not be wise anyway.

      Delete
  4. Hi Peter,

    Someone I know is taking 700mg of Cocoavia per day. He is not autistic, but has other neurological/psychiatric issues, including slowing of working memory (though not evident in neuropsych testing), mild depression. His thyroid antibodies are very high with euthyroid, and the diagnosis is maybe Hashimoto's encephalopathy, not thyroiditis. He is due for a course of i.v. steroids and his response to that will confirm diagnosis. He is a highly intelligent person, been an executive, but is struggling a bit at work now. He also had a quadruple bypass earlier this year, was the youngest the hospital had had for the surgery. He reports feeling 'bright' with the cocoavia, some improvement of symptoms, says it is a keeper. He does seem a bit better, and there seem to be both acute and cumulative effects. He is planning on increasing to 1gm, will keep you updated.

    Many thanks for your input.

    ReplyDelete
    Replies
    1. I think most older people would benefit from Cocoavia and I think that Mars will make a big business out of it. Good for them.

      Delete
  5. I live in the USA and ordered the Mars Cocoavia (sweetened chocolate flavor with 375mg of flavanols per packet). Unfortunately, my 8 year old son hates the taste and spit it out even though I mixed it up in a smoothie. I'd also tried PharmaNAC a few months ago and he had the same reaction. (Reviews of both products are mixed with some loving the taste and others hating it.) I tired it myself and I don't care for the taste- but it's ok when I take it with tea. I don't know if it's true but I read one review of the product, which claims heat reduces the flavanol content and it's better to eat it cold.
    Regards,
    RD

    ReplyDelete
    Replies
    1. The answer is probably to learn how to swallow pills. I put off trying to do this for years, assuming it would be hard, but it was not.

      One parent I met a long time ago told me that she made a big point of teaching here two kids with autism how to swallow pills. She was right.

      Practical tips to make it easier to swallow strange tasting liquids include using a straw (minimizes the taste), giving a reward for drinking the medicine and to start with a mild taste and gradually make it stronger. My son had all these issues, but will now drink almost anything if I tell him it is medicine and he gets a gummy bear.

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    2. I ordered the unsweetened cocoa via powder, they come in individual packs. Can be mixed into some cream and sweetener of choice for a lovely pudding. Or pannacotta. I also had it as a not very hot chocolate, just warmed some milk and honey and added the powder to it. Quite good. I think the problem with the sweetened version is the artificial sweetener that your son may not like the taste of.

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  6. I loved your article. As a mom of an adult autistic child, I was grasping at straws to help me. Among other things he was a poor eater. I cam across Healthy Chocolate Co. Xocai unheated chocolates. Their healthy chocolate seems to provide many health benefits for our family. When they came out with the Xocai protein shake with 56,500 ORACfn and 1,128 flavonoids per meal, I tried it for my son with very promising results. He has this shake every morning for breakfast. Not recommended to be used with milk. His morning shake consists of 2 scoops Xocai protein shake, 1 cup ice, 1 cup water, 1/2 frozen banana and a touch of peanut butter. His follow up consisted of quarterly appointments with his specialist who appaeared to notice a benefit in the office of eye contact, better mood and attention. He has been on this shake every morning for the last four years. Benefits we see include muxh better eye contact, talking not just to us but others and greatly improved mood. He is now 24 years old and we expect he will have this every day for life. We continue to see improvements. If you would like to try Xocai Healthy Chocolate, I would be happy to send you a sample. This has been a lifechanger for us as our son used to have severe outbursts that once caused me to have a broken right shoulder and left arm from being pushed. You are on to something as unheated chocolate, cocoa flavanols and antioxidants are making a difference for our autistic son. It almost seems like he is detoxing.

    ReplyDelete
  7. Peter, Came across this and was wondering if you think there is some validity to their argument? https://www.vox.com/science-and-health/2017/10/18/15995478/chocolate-health-benefits-heart-disease

    ReplyDelete
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    1. The flavanols in cocoa have proven health benefits, but the rest of the ingredients in chocolate are not helpful. Rather than eat high cocoa content chocolate, better to eat just the high flavanol cocoa or the extracted flavanols. High flavanol cocoa does not taste so good and so to make chocolate the processing destroys the flavanols but improves the taste.

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