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Showing posts with label AMD. Show all posts
Showing posts with label AMD. Show all posts

Friday, 1 June 2018

Autism, Power Outages and the Starving Brain?



There are certain Critical Periods in the development of the human brain and these are the most vulnerable times to any genetic or environmental insult.  Critical Periods (CPs) will be the subject of post appearing shortly.


Another power outage waiting to happen

 Have you wondered why autism secondary to mitochondrial disease (regressive autism) almost always seem to occur before five years of age, and usually much earlier?  Why does it not happen later? Why is it's onset often preceded by a viral infection?
I think you can consider much of this in terms of the brain running out of energy. Humans have evolved to require a huge amount of energy to power their developing brains, a massive 40% of the body’s energy is required by the brain in early childhood.  If your overload a power grid it will end in a blackout.
We know many people with autism have a tendency towards mitochondrial dysfunction, they lack some key enzyme complexes. This means that the process of OXPHOS (Oxidative phosphorylation), by which the body converts glucose to usable energy (ATP), is partially disabled. 

We saw in earlier posts how the supply of glucose and oxygen to the brain can be impaired in autism because there is unstable blood flow.


It is just like in your house, all your electrical appliances might mean you need a 25KW supply, because you do not use them all at the same time. Just to be on the safe side you might have a 40KW limit. What if the power company will only give you a 20 KW connection? If you turn on the clothes drier, the oven, the air conditioning and some other things all of a sudden you blow the main fuse and perhaps damage the hard drive of your old computer.
So, in the power-hungry brain of a three-year-old, you add a viral infection and all of a sudden you exceed the available power supply from the mitochondria, that have soldered on for 3years with impaired supply of complex 1 and imperfect cerebral blood flow. By the sixth year of life, the peak power requirement from the brain would have fallen to within the safe limit of the mitochondria and its impaired supply of complex 1.  Instead of blowing the fuse, which is easy to reset, you have blown some neuronal circuitry, which is not so easy to repair.    

Too Many Synapses?
We know that it is the synapses in the brain that are the big energy users and we also know that in most autism there are too many synapses. So, in that group of autism there is an even bigger potential energy demand.



Note that in Alzheimer’s type dementia (AD in the above chart) you see a severe loss of synapses/spines as atrophy takes place. This occurs at the same time as a loss of insulin sensitivity occurs (type 3 diabetes). Perhaps the AD brain is also starved of energy, it does seem to respond to ketosis (ketones replacing glucose as the fuel) and it responds to Agmatine (increasing blood flow via eNOS).
We also know that adolescent synaptic pruning is dysfunctional in autism and we even know why. Interestingly by modifying GABAA function with bumetanide we may indeed allow the brain to eliminate more synapses (a good thing), so possibly an unexpected benefit from Ben Ari’s original idea.

"Working with a mouse model we have shown that, at puberty, there is an increase in inhibitory GABA receptors, which are targets for brain chemicals that quiet down nerve cells. We now report that these GABA receptors trigger synaptic pruning at puberty in the mouse hippocampus, a brain area involved in learning and memory." The report, published by eLife, "Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines."            
These findings may suggest new treatments targeting GABA receptors for "normalizing" synaptic pruning in diseases such as autism and schizophrenia, where synaptic pruning is abnormal. Research has suggested that children with autism may have an over-abundance of synapses in some parts of the brain.

Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4βδ GABAA receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4βδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4βδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4βδ GABARs. In their absence, pruning is prevented and cognition is not optimal.


Strange Patterns of Growth
Longitudinal studies are when researchers collect the same data over long period of years. Most autism research is just based on a single snapshot in time.
One observation of mine is that some people with strictly defined autism (SDA) are born at the 90+ percentile for height, but then fall back to something like the 20 percentile. Body growth has dramatically slowed. Was this because energy has been diverted to the overgrowing brain? 
A five-year old’s brain is an energy monster. It uses twice as much glucose (the energy that fuels the brain) as that of a full-grown adult, a new study led by Northwestern University anthropologists has found.
It was previously believed that the brain’s resource burden on the body was largest at birth, when the size of the brain relative to the body is greatest. The researchers found instead that the brain maxes out its glucose use at age 5. At age 4 the brain consumes glucose at a rate comparable to 66 percent of the body’s resting metabolic rate (or more than 40 percent of the body’s total energy expenditure). 

“The mid-childhood peak in brain costs has to do with the fact that synapses, connections in the brain, max out at this age, when we learn so many of the things we need to know to be successful humans,” Kuzawa said.

“At its peak in childhood, the brain burns through two-thirds of the calories the entire body uses at rest, much more than other primate species,” said William Leonard, co-author of the study. “To compensate for these heavy energy demands of our big brains, children grow more slowly and are less physically active during this age range. Our findings strongly suggest that humans evolved to grow slowly during this time in order to free up fuel for our expensive, busy childhood brains.” 

Full paper: -


The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain’s glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain–body metabolic trade-offs using the ratios of brain glucose uptake to the body’s resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate. 

To quantify the metabolic costs of the human brain, in this study we used a unique, previously collected age series of PET measures of brain glucose uptake spanning birth to adulthood (32), along with existing MRI volumetric data (36), to calculate the brain’s total glucose use from birth to adulthood, which we compare with body growth rate. We estimate total brain glucose uptake by age (inclusive of all oxidative and nonoxidative functions), which we compare with two measures of whole-body energy expenditure: RMR, reflecting maintenance functions only, and daily energy requirements (DER), reflecting the combination of maintenance, activity, and growth. We hypothesized that ages of peak substrate competition (i.e., competition for glucose) between brain and body would be aligned developmentally with the age of slowest childhood body growth, and more generally that growth rate and brain glucose use would covary inversely during development, as is predicted by the concept of a trade-off between brain metabolism and body growth in human life-history evolution. 

Daily glucose use by the brain peaks at 5.2 y of age at 167.0 g/d and 146.1 g/d in males and females, respectively. These values represent 1.88- and 1.82-times the daily glucose use of the brain in adulthood (Fig. 1 A and B and SI Appendix, Fig. S2), despite the fact that body size is more than three-times as large in the adult.




Glucose use of the human brain by age. (A) Grams per day in males. (B) Grams per day in females; dashed horizontal line is adult value (A and B). (C) Glucosermr% (solid line) and glucoseder% (dashed line) in males. (D) Glucosermr% (solid line) and glucoseder% (dashed line) in females.

The most relevant data is the line highlighted in yellow below, showing brain consumption of glucose peaks at 40% (of total body consumption) around 5 years old and drops to 20% in adulthood.

Our findings agree with past estimates indicating that the brain dominates the body’s metabolism during early life (31). However, our PET-based calculations reveal that the magnitude of brain glucose uptake, both in absolute terms and relative to the body’s metabolic budget, does not peak at birth but rather in childhood, when the glucose used by the brain comprises the equivalent of 66% of the body’s RMR, and roughly 43% of total expenditure. These findings are in broad agreement with past clinical work showing that the body’s mass-specific glucose production rates are highest in childhood, and tightly linked with the brain’s metabolic needs (40). Whereas past attempts to quantify the contribution of the brain to the body’s metabolic expenditure suggested that the brain accounted for a continuously decreasing fraction of RMR as the brain-to-body weight ratio declined with age (25, 31), we find a more complex pattern of substrate trade-off. Both glucosermr% and glucoseder% decline in the first half-year as a fast but decelerating pace of body growth established in utero initially outpaces postnatal increases in brain metabolism. Beginning around 6 mo, increases in relative glucose use are matched by proportionate decreases in weight growth, whereas ages of declining brain glucose uptake in late childhood and early adolescence are accompanied by proportionate increases in weight growth. The relationships that we document between age changes in brain glucose demands and body-weight growth rate are particularly striking in males, who maintain these inverse linear trends despite experiencing threefold changes in brain glucose demand and body growth rate between 6 mo and 13 y of age. In females, an earlier onset of pubertal weight gain leads to earlier deviations from similar linear inverse relationships.
                                     

What the researchers then did was to see how the growth rate of the brain is correlated to the growth rate of the body. In effect that what they found was that the growth of the body has to slow down to allow the energy hungry brain to develop.  One the brain has passed its peak energy requirement at about 5 years old, body growth can then gradually accelerate. 
The brain is the red line, the body is blue. The chart on the left is males and the one on the right is females. 
So, we might suspect that in 2 to 4-year olds who seem not to be growing as fast as we might expect, the reason is that their brain is over-growing, a key feature of classic autism.

Glucoseder% and body-weight growth rate. Glucoseder% and weight velocities plotted as SD scores to allow unitless comparison. (A) Glucoseder% (red dots) and dw/dt (blue dots) by age in males. (B) Glucoseder% (red dots) and dw/dt (blue dots) by age in females


Brain Overgrowth in Autism
As has been previous commented on in this blog, Eric Courchesne has pretty much figured out what goes wrong in the growth trajectory of the autistic brain; that was almost 15 years ago.

Brain development in autism: early overgrowth followed by premature arrest of growth.


Author information


Abstract


Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies have now shown that abnormal brain overgrowth occurs during the first 2 years of life in children with autism. By 2-4 years of age, the most deviant overgrowth is in cerebral, cerebellar, and limbic structures that underlie higher-order cognitive, social, emotional, and language functions. Excessive growth is followed by abnormally slow or arrested growth. Deviant brain growth in autism occurs at the very time when the formation of cerebral circuitry is at its most exuberant and vulnerable stage, and it may signal disruption of this process of circuit formation. The resulting aberrant connectivity and dysfunction may lead to the development of autistic behaviors. To discover the causes, neural substrates, early-warning signs and effective treatments of autism, future research should focus on elucidating the neurobiological defects that underlie brain growth abnormalities in autism that appear during these critical first years of life.


Research from 2017: -





Conclusion
A record of children’s height and weight and even head circumference is usually collected by their doctor. In an earlier post I did ask why they bother if nobody is checking this data. If a child falls from the 90th percentile in height to the 20th, something clearly is going on.
When I discussed this with a pediatric endocrinologist a few years ago, we then measured bone-age and IGF-1. If you have low IGF-1 and retarded bone age you might opt for some kind of growth hormone therapy.
In what is broadly defined as autism, I think we have some distinctly different things possibly happening: -

Group AMD
Energy conversion in the brain is less efficient than it should be due to a combination of impaired vascular function and impaired mitochondrial enzyme complex production. No symptoms are apparent and developmental milestones are achieved.  As the brain creates more synapses it energy requirement grows until the day when the body has some external insult like a viral infection, and the required power is not available, triggering a “power outage” which appears as the regression into autism. In biological terms there has been death of neurons and demyelination.

Group Sliding Down the Percentiles 
This group looks like a sub-set of classic autism. The brain grows too rapidly in the first two years after birth and this causes the expected slowing of body growth to occur much earlier than in typical children. This manifests itself in the child tumbling down the percentiles for height and weight.
The brain then stops growing prematurely, reducing energy consumption and allowing body growth to accelerate and the child slowly rises back up the height/weight percentiles.

Perhaps all those excessive synapses that were not pruned correctly are wasting glucose and so delay the growth of the rest of the body?   
In the sliding down the growth percentiles group, does this overgrowing brain ever exceed maximum available power? Maybe it just grows too fast and so mal-develops, as suggested by Courchesne, or maybe it grows too fast and cannot fuel correct development?  What happens if you increase maximum available power in this group, in the way some athletes use to enhance their performance/cheat?
All I know for sure is that in Monty, aged 14 with autism, increasing eNOS (endothelial nitric oxide synthase) using agmatine seems to make him achieve much more, with the same daily glucose consumption. I wonder what would happen if Agmatine was given to very young children as soon as it was noted that they were tumbling down the height percentiles?  This is perhaps what the pediatric endocrinologists should be thinking about, rather than just whether or not to administer growth hormones/IGF-1.
If you could identify Group AMD before the “power outage” you might be able to boost maximum power production or reduce body growth slightly and hence avoid the brain ever being starved of energy. That way you would not have most regressive autism.







Friday, 29 December 2017

Childhood Disintegrative Disorder (CDD) – Not a Useful Diagnosis?


Today’s post is about CDD (Childhood Disintegrative Disorder) also known as Heller’s Syndrome, which sounds rather nicer. It was first identified in 1908 by an Austrian, Theodore Heller. Later on came Hans Asperger, another Austrian and Leo Kanner who was born in what was the Austro-Hungarian Empire.

Why were Austrians so interested in Autism?

I started this post expecting that I would naturally be a supporter of the continued use of CDD as a diagnosis, I do firmly support calling an Aspie an Aspie after all. 
CDD is a diagnosis used for late onset severe regressive autism, which has fast onset, making it scary for all concerned.
Unlike many syndromes, Rett for example, Heller’s syndrome is not a defined genetic condition, it is just another observational diagnosis. This probably explains why it has been folded into the ASD diagnosis in the current DSM5, which sadly was also the case with Asperger’s.
Since it is not really a syndrome I will call it by its other name CDD (Childhood Disintegrative Disorder). I have not previously given much mention to CDD in my blog because I had assumed it was much worse than “regular” severe autism and that the disorder was well defined, so that it would be a clear case of CDD or autism.  It turns out this was a mistake. 

Back in 1994
In 1994 when Yale researcher, Fred Volkmar, was writing about CDD and severe autism he noted
More boys than girls appear to be affected. Childhood disintegrative disorder is perhaps 10 times less common than more strictly defined autism and is estimated to occur in between 1-2 children per 100,000. 


He was thinking strictly defined autism (SDA) was present in 0.015% of the population (15 children per 100,000), whereas I think today it is 0.3% (300 children per 100,000). I have got by zeroes in the right place. That is a massive twenty-fold increase in severe autism in 20 years, something that is never seriously investigated because DSM5 autism now includes 1% (1,000 children per 100,000) who have mild autism (mainly Asperger’s), so no statistics are directly comparable. 

Present Day
In today’s post we will see that CDD is just another broad umbrella term for a large number of different, often genetic, disorders. The case of CDD presented by a Yale researcher below appears to show a young lady less severely affected than many people with a diagnosis of severe autism. 

Well in case of Gina in the above article, it looks no worse than “regular” severe autism, certainly not terrifying. She rides a bicycle and helps around the home.

The Yale researcher in the above article is rather indignant that his disorder has “disappeared” into autism in DSM5 and so now he struggles to get funding.  What is telling is his comment that if you had a CDD diagnosis, clinicians would then naturally look for its biological origin, but now with a diagnosis of autism with ID (Intellectual Disability), no clinician will investigate further. Why is that??
The distinction has clinical implications. With a CDD diagnosis, the initial push is to hunt for a reversible cause. If the patient is diagnosed with autism and intellectual disability instead, that hunt never happens. "This means we may be missing a whole world of possible treatments for kids on the low-functioning end," says Westphal. 

Now this raises a question of why people with CDD are more worthwhile investigating, than anyone else. Surely all cases of severe autism should be investigated? There are no more wonder cures for CDD than there are for any other autism. As we have seen previously, there are numerous rare inborn errors of the metabolism that cause autism/ID that are treatable. 
Westphal wrongly assumes that there are no possible therapies for severe idiopathic autism. 

CDD as a sub-type of regressive autism
It would seem best to consider CDD for what it is, late onset regressive autism, with or without a “prodrome”, which is a distressing period of great anxiety lasting a month or two as the regression from normal to severe autism takes place.
In the young lady profiled in the above article, there was no prodrome and her regression took place at 3 years old and left her in a condition better than some I know with an autism diagnosis.
So here I actually agree with DSM5 that she would be better off with an autism + ID diagnosis; she should then have been taken to Johns Hopkins to see Dr Kelley, to check for mitochondrial disease. She looks no different to one of his cases of severe autism secondary to mitochondrial disease (AMD).
It looks like genuinely late regression, say 5 to 10 years old, points to some rare disorders like leukodystrophy, which is itself a family of genetic myelination disorders. These can be late onset and are degenerative.
Very likely within what has been diagnosed as CDD are hundreds of rare disorders, some degenerative but most not. It is the degenerative potential that makes CDD scary, but most people do not have this.
Some of these non-degenerative disorders will overlap with people diagnosed with severe autism, which itself likely includes many hundreds of rare biological disorders.
It certainly is important to get as precise diagnosis/description of each type of autism as possible.
So why not keep CDD along with Asperger’s as sub-categories of autism? All these rather vague observational diagnosis carry risks. You can have mitochondrial disease at age 5 that causes a regression to severe autism, I think the Yale team might well (mis)diagnose that as CDD, which is much more of an arbitrary diagnosis than I had realized.
An important issue is whether the disfunction is degenerative or not. It turns out that in a small number of CDD cases, the disintegration continues to an early death, but in most cases the condition becomes stable and in a small number of cases there is partial recovery, as with Dr Kelley’s AMD. This tells us that the observational diagnosis is pretty pointless. As always, what matters is a biological diagnosis.
The CDD researchers think some people with severe autism have CDD. I think people with CDD either have a rare genetic dysfunction, which may or may not be degenerative, they have mitochondrial disease, or it is “just” another case of idiopathic autism (the “I don’t know” category). So I do not really see the point of the CDD diagnosis.
The diagnosis should be ASD, its severity, speech delay or not, cognitive level, nature and time of onset, and then possible biological origin based on genetic testing. 

Conclusion
I think people diagnosed with CDD, who have no identifiable genetic disorder, really need to get tested for mitochondrial disease.
I wish some more intelligent people were in charge of autism research and collecting and interpreting data on prevalence. Is it possible that the prevalence of Strictly Defined Autism (SDA) was just 0.015% in 1994, versus 0.3% today? That means going from very rare to just rare in two decades. Maybe clinicians back then diagnosed a much larger group simply with MR/ID, that today would get diagnosed with autism + MR/ID. Pre Dr Wakefield and the MMR vaccine scandal, autism was rarely spoken about, even among doctors; today it has become quite a fashionable diagnosis. That is the best explanation I can think of; we do know that the diagnosis of MR/ID has fallen substantially in the last decades. 



Friday, 7 April 2017

Treating Mitochondrial Disease/Dysfunction in Autism


In my book I will be covering the science behind hopefully almost all autism, which then naturally leads to translating it into therapy.  In the ideal world you would just skip straight to the therapy and the final section of the book will be just that.  Clearly it would make sense to read the science first, so that you know what are the dysfunctions that you might need to treat.

Hopefully there will also be some case studies from people who have applied a science-based approach to identify and implement effective therapies.

Roger would clearly make a very good example of a reversible in-born metabolic-caused type of autism.

I will be posting on my blog some drafts from the Part III - Translating Science to Treat Autism.  This is of course just one person's collection of other people's ideas and some of his one.  The reader and his/her medical medical team ultimately decide what to implement and must monitor its ongoing implementation.

 * * *


Mitochondrial disease is managed rather than cured. It seems to be present in autism in widely varying degrees of severity.  Extreme cases result in very severe regressive autism with MR/ID.

It is either diagnosed based on detailed analysis of numerous blood tests, or more recently via a sample taken from inside the cheek. These tests cannot be perfect, because mitochondrial disease can be organ-specific.

Someone with body-wide mitochondrial disease will have poor exercise endurance and this will be very noticeable compared to siblings and peers.

Dr Kelley, from Johns Hopkins, has published his therapy for autism secondary to mitochondrial disease (AMD):-

1.      Augment residual mitochondrial enzyme complex I activity

2.      Enhance natural systems for protection of mitochondria from reactive oxygen species

3.      Avoid conditions known to impair mitochondrial function or increase energy demands, such  as prolonged fasting, inflammation, and the use of drugs that inhibit complex I.

Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

L-Carnitine 50 mg/kg/d                Alpha Lipoic acid 10 mg/kg/d

Coenzyme Q10 10 mg/kg/d          Pantothenate 10 mg/kg/d

Vitamin C 30 mg/kg/d                  Nicotinamide 7.5 mg/kg/d (optional)

Vitamin E 25 IU/kg/d                   Thiamine 15 mg/kg/d (optional)


There are actually five stages in the OXPHOS process in mitochondria and there are five enzyme complexes. Dr Kelley's plan above is for the most common dysfunction, complex 1.

Different clinicians have different treatments.

Also appearing elsewhere are :-

Calcium folinate (2 x 25 mg), but not because of peroxynitrite

Biotin 5-10 mg/day

NAC

Methylcobalamin B12

Creatine


On the basis that peroxynitrite, from nitrosative stress, damages the mitochondria, you might consider:

·         Calcium folinate (leucoverin) in very high doses like 25mg twice a day.

·         Xanthine oxidase inhibitors, typically used to lower uric acid to treat gout. A good example is Allopurinol. It will both lower uric acid and peroxynitrite. Uric acid is itself a potent scavenger of peroxynitrite; this may look odd given the previous sentence. If someone has low uric acid and wants to reduce peroxynitrite then uric acid itself should be therapeutic. The purine metabolism may play a key role in some types of autism, as proposed by Professor Robert Naviaux.

·         Rosmarinic acid, a natural scavenger of peroxynitrite.

There are many anomalies in autism and one is uric acid.  Some people have low levels and some have high levels. Uric acid is itself a scavenger of peroxynitrite.  People with high levels of uric acid do get gout, but almost never MS (multiple sclerosis) and it has been suggested that scavenging peroxynitrite is neuroprotective.

Special, electrically charged, antioxidants have been developed to target the mitochondria.  MitoE is a charged version of vitamin E and MitoQ is a charged version of coenzyme Q10.

Based on the research, you might  also seek to activate PGC-1α, the master regulator of mitochondrial biogenesis. This can potentially be achieved via:-


·         Exercise  (gradual endurance training)

·         Activate PPARγ and perhaps  PPARα (e.g. Bezafibrate  and Rosiglitazone)

·         Activate AMPK (Metformin)

·         Activate Sirt-1 (resveratrol and other polyphenolic ‎compounds)


Carnitine-like analogs may also help in theory.  The standard L-Carnitine, widely used as a supplement, is very poorly absorbed even at high doses. An analog is a modified version of a molecule that keeps the therapeutic beneficial effect, but overcomes a drawback, bioavailability in the case of carnitine. There is some basis in the literature to believe that the Latvian drug Mildronate might be useful to treat complex 1 mitochondrial dysfunction.



more detail at  https://epiphanyasd.blogspot.com/2017/02/mitochondrial-disease-and-autsim.html



Wednesday, 18 January 2017

The Clever Ketogenic Diet for some Autism


I have covered the Ketogenic Diet (KD) in earlier posts. 

There are more and more studies being published that apply the KD to mouse models of autism.

Calling the KD a diet does rather under sell it.  The classic therapeutic ketogenic diet was developed for treatment of pediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective epilepsy drugs.

There are various exclusion diets put forward to treat different medical conditions; some are medically accepted but most are not, but that does not mean they do not benefit at least some people.

When it comes to the ketogenic diet (KD) the situation is completely different, this diet is supposed to be started in hospital and maintained under occasional medical guidance. The KD was developed as a medical therapy to treat pediatric epilepsy.  It is very restrictive which is why it is used mainly in children, since they usually will (eventually) eat what is put in front of them.

The KD was pioneered as a medical therapy by researchers at Johns Hopkins in the 1920s, over the years they have shown that most of the benefit of the KD can be achieved by the much less restrictive Modified Atkins Diet (MAD).  The first autism mouse study below suggests something similar “Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior”.


What about the KD in Autism?

Most people with autism, but without epilepsy, will struggle to get medical help to initiate the KD.  Much research in animal models points to the potential benefit of the KD.




·        Drug treatments are poorly effective against core symptoms of autism.


·        Ketogenic diets were tested in EL mice, a model of comorbid autism and epilepsy.


·        Sociability was improved and repetitive behaviors were reduced in female mice.


·        In males behavioral improvements were more limited.


·        Metabolic therapy may be especially beneficial in comorbid autism and epilepsy.


The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.






·        The BTBR mouse has lower movement thresholds and larger motor maps relative to control mice.


·        The high-fat low-carbohydrate ketogenic diet raised movement thresholds and reduced motor map size in BTBR mice.


·        The ketogenic diet normalizes movement thresholds and motor map size to control levels.


Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder characterized by deficits in sociability and communication, and restricted and/or repetitive motor behaviors. Amongst the diverse hypotheses regarding the pathophysiology of ASD, one possibility is that there is increased neuronal excitation, leading to alterations in sensory processing, functional integration and behavior. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used in the treatment of medically intractable epilepsy, has already been shown to reduce autistic behaviors in both humans and in rodent models of ASD. While the mechanisms underlying these effects remain unclear, we hypothesized that this dietary approach might shift the balance of excitation and inhibition towards more normal levels of inhibition. Using high-resolution intracortical microstimulation, we investigated basal sensorimotor excitation/inhibition in the BTBR T + Itprtf/J (BTBR) mouse model of ASD and tested whether the KD restores the balance of excitation/inhibition. We found that BTBR mice had lower movement thresholds and larger motor maps indicative of higher excitation/inhibition compared to C57BL/6J (B6) controls, and that the KD reversed both these abnormalities. Collectively, our results afford a greater understanding of cortical excitation/inhibition balance in ASD and may help expedite the development of therapeutic approaches aimed at improving functional outcomes in this disorder.





Background

Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBRT + tf/j (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile.

Findings

Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10–14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals.

Conclusions

Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.





·        We evaluated, throughout a systematic review, the studies with a relationship between autism and ketogenic diet.


·        Studies points to effects of KD on behavioral symptoms in ASD through the improve score in Childhood Autism Rating Scale (CARS).


·        Reviewed studies suggest effects of KD especially in moderate and mild cases of autism.


·        KD in prenatal VPA exposed rodents, as well in BTBR and Mecp2 mice strains, caused attenuation of some autistic-like features.



Autism spectrum disorder (ASD) is primarily characterized by impaired social interaction and communication, as well as restricted repetitive behaviours and interests. The utilization of the ketogenic diet (KD) in different neurological disorders has become a valid approach over time, and recently, it has also been advocated as a potential therapeutic for ASD. A MEDLINE, Scopus and Cochrane search was performed by two independent reviewers to investigate the relationship between ASD and the KD in humans and experimental studies. Of the eighty-one potentially relevant articles, eight articles met the inclusion criteria: three studies with animals and five studies with humans. The consistency between reviewers was κ = 0.817. In humans, the studies mainly focused on the behavioural outcomes provided by this diet and reported ameliorated behavioural symptoms via an improved score in the Childhood Autism Rating Scale (CARS). The KD in prenatal valproic acid (VPA)-exposed rodents, as well as in BTBR and Mecp2 mice strains, resulted in an attenuation of some autistic-like features. The limited number of reports of improvements after treatment with the KD is insufficient to attest to the practicability of the KD as a treatment for ASD, but it is still a good indicator that this diet is a promising therapeutic option for this disorder.



Conclusion

Since very many parents do not want to use drugs to treat autism, it is surprising more people do not try the ketogenic diet (KD) or at least the KD-lite, which is the Modified Atkins Diet (MAD).
I think you have to be pretty rigid about the MAD, if you go MAD-lite you will likely achieve little; rather like thinking you have a Mediterranean diet because you buy the occasional bottle of olive oil.
Many children with epilepsy who started out on the KD continue in adulthood with the Modified Atkins Diet (MAD).
There is anecdotal evidence that people with mitochondrial disease benefit from the KD.
All in all, it is hard to argue that the KD/MAD should not be the first choice for those choosing to treat autism by diet. It really does have science and clinical study to support it.

In some people with autism it appears that when you eat is as important as what you eat.  There can be strange behaviors just after eating, presumably caused by a spike in blood sugar, or for others before breakfast. 

In regressive autism (AMD) Dr Kelley, from Johns Hopkins, wrote that:- 


Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.  In some children, early morning symptoms can be a consequence of compromised mitochondrial function, whereas, in others, a normal rise in epinephrine consequent to a falling blood glucose level in the early morning hours can elicit agitation, ataxia, tremors, or difficulty waking.  In children who normally sleep more than 10 hours at night, significant mitochondrial destabilization can occur by the morning and be evident in biochemical tests, although this is less common in AMD than in other mitochondrial disorders.  When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period.  Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours.



I still find it rather odd that none of Dr Kelley's work on treating regressive autism has been published in any scientific or medical journal.  After all, he was a leading staff member at one of the world's leading hospitals.  He is no quack.  It is extremely wasteful of knowledge and clinical insights that could help improve the lives of something greater than 0.2% of the world's young children.  That is a lot of people.












Tuesday, 8 March 2016

Meldonium/Mildronate for Athletic Performance, but seemingly also for Mitochondria, Neuroinflammation, Cognition and Alzheimer’s





What you see is what you get,
not what you see is what he took.



Today’s post is another very short one.

You may have seen that Maria Sharapova, the tennis player has got into trouble for taking a Latvian drug called Meldonium/Mildronate for the last decade.


Like many people, I did a quick check on this drug to see what it does and if you could innocently not know that it is performance enhancing.  Well it does lots of performance enhancing things like increasing blood flow and increasing your capacity to exercise.


What drew my attention was its effect on mitochondria, cognition and even as a potential Alzheimer’s Therapy.

I should point out that Bumetanide, the most effective Autism therapy my son uses, is also a banned substance under the World Doping Agency rules.  Bumetanide and other diuretics are used as masking agents by athletes taking performance enhancing drugs.  


Mildronate

Mildronate is a Latvian drug, widely prescribed across the former Soviet Union.

For people with autism who respond to carnitine therapy, or with a diagnosed mitochondrial disorder it looks very interesting.  There really are no approved treatments that reverse such disorders, just to stop them getting worse.

Mildronate also shows some promise for both Parkinson’s and Alzheimer’s disease in animal models.


Mildronate improves cognition and reduces amyloid-β pathology in transgenic Alzheimer's disease mice

 

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-β deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-β pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients.





This review for the first time summarizes the data obtained in the neuropharmacological studies of mildronate, a drug previously known as a cardioprotective agent. In different animal models of neurotoxicity and neurodegenerative diseases, we demonstrated its neuroprotecting activity. By the use of immunohistochemical methods and Western blot analysis, as well as some selected behavioral tests, the new mechanisms of mildronate have been demonstrated: a regulatory effect on mitochondrial processes and on the expression of nerve cell proteins, which are involved in cell survival, functioning, and inflammation processes. Particular attention is paid to the capability of mildronate to stimulate learning and memory and to the expression of neuronal proteins involved in synaptic plasticity and adult neurogenesis. These properties can be useful in neurological practice to protect and treat neurological disorders, particularly those associated with neurodegeneration and a decline in cognitive functions.

The obtained data give a new insight into the influence of mildronate on the central nervous system. This drug shows beneficial effects in the regulation of cell processes necessary for cell integrity and survival, particularly by targeting mitochondria and by stabilizing the expression of proteins involved in neuroinflammation and neuroregeneration. These properties can be useful in neurological practice to protect and treat neurological disorders, such as Parkinson’s disease, diabetic neuropathies, and ischemic stroke. Moreover, because mildronate improves learning and memory, one may suggest mildronate as a multitargeted neuroprotective/ neurorestorative drug with its therapeutic utility as a memory enhancer in cognitive impairment conditions, such as neurodegenerative diseases, schizophrenia, and other pathologies associated with a decline in awareness.



Mildronate, a representative of the aza-butyrobetaine class of drugs with proven cardioprotective efficacy, was recently found to prevent dysfunction of complex I in rat liver mitochondria. The present study demonstrates that mildronate also acts as a neuroprotective agent. In a mouse model of azidothymidine (anti-HIV drug) neurotoxicity, mildronate reduced the azidothymidine-induced alterations in mouse brain tissue: it normalized the increase in caspase-3, cellular apoptosis susceptibility protein (CAS) and iNOS expression assessed by quantitative and semi-quantitative analysis. Mildronate also normalized the changes in cytochrome c oxidase (COX) expression, reduced the expression of glial fibrillary acidic protein (GFAP) and cellular infiltration. The present results show that the neuroprotective action of mildronate results at least partially from anti-neurodegenerative (anti-apoptotic) and anti-inflammatory mechanisms. It might be suggested that the molecular conformation of mildronate can facilitate its easy binding to mitochondria, and regulate the expression of different signal molecules, hence maintaining cellular signaling and survival.



Conclusion

If any of the Russian readers of this blog have trialed Mildronate in their child with autism secondary to mitochondrial disease (AMD), please let us know the result.


Perhaps Dr Kelley should try mildronate, it clearly falls into his area of interest.