Regressive Autism and Mitochondria - Part 1

This blog is mainly about classic early-onset autism and the biology underlying it.

There are many other disorders that also result in autistic behaviours, some of which are much better understood than classic autism.  Today’s post is about Mitochondrial Disease which appears to be the precursor to most cases of regressive autism, according to Dr Richard Kelley, at Johns Hopkins and the Kennedy Krieger Institute.

In well-resourced centers for autism, by which I mean large teaching hospitals in the US, cases of autism are often fully investigated.  First they rule out mitochondrial disease and common known single gene causes like Fragile X.  Next comes the chromosome microarray. The microarray (often referred to as CMA) may identify a genetic cause in 15-20% of individuals with an ASD. 

In the rest of the world no such testing takes place, unless you are very lucky.

If the supplement Carnitine makes you feel better, read on, because you quite likely have some mitochondrial dysfunction and have Asperger’s secondary to Mitochondrial Disease.

If you are interested in regressive autism and particularly if you live outside the US, this post could be very relevant.

In short, medical testing can establish whether mitochondrial disease is present.  If it is present, it may be the underlying cause of the regressive autism, or perhaps just an aggravating factor.  If steps are taken quickly, further damage can be limited and the final outcome much improved.

Some of the therapies are the same as for classic autism, like anti-oxidants but some are the opposite.

Certain common drugs should be avoided like types of painkiller (Tylenol/ acetaminophen/paracetamol and aspirin), statins, steroids, valproic acid, risperidone (Risperdal), haloperidol, and some SSRIs; all are inhibitors of complex I / toxic to mitochondria.

There is at least one emerging drug therapy to treat the mitochondria, as opposed to just limit further damage.

The following extensive extracts are all from a paper by Dr Richard Kelley, at the Kennedy Krieger Institute and the neighboring Johns Hopkins Hospital.  I suggest reading the full original paper.  It is the most useful paper related to autism that I have come across, and that is thousands of papers.

Autism secondary to Mitochondrial Disease (AMD)

Evaluation and Treatment of Patients with Autism and Mitochondrial Disease

Most children with autism secondary to mitochondrial disease (“AMD”) experience a single episode of injury, while a few suffer two or more periods of regression during a characteristic window of vulnerability between 12 and 30 months. The subsequent natural history of AMD is typical for regressive autism, with most children showing partial recovery between 3 and 10 years. The principal clinical differences between AMD and non-regressive autism are, variably, a mild myopathy, abnormal fatigue, and, occasionally, minor motor seizures in the years following the first episode of injury. Others with biochemically defined AMD experience a period of only developmental stagnation lasting several months or more between ages 12 and 30 months and show overall better recovery than those who experience a severe autistic regression during this period of neurological fragility. More noteworthy, but uncommonly identified, are sibs of AMD individuals who have all the biochemical features of AMD with no or only minimal developmental or behavioral abnormalities, such as ADHD or obsessive-compulsive disorder.

While permanent developmental losses in AMD can be substantial, especially in the few individuals who suffer more than one episode of regression, recovery can be almost complete in some children when treatment is started early after the first episode of regression, and a partial response to metabolic therapy remains possible indefinitely. Treatment of AMD includes augmentation of residual complex I activity with carnitine, thiamine, nicotinamide, and antothenate, and protection against free radical injury with several antioxidants, including vitamin C, vitamin E, alpha-lipoic acid, and coenzyme Q10 (CoQ10).

Although a deficiency of mitochondrial complex I may be the most common identifiable cause of regressive autism, the relatively mild biochemical abnormalities often are missed by “routine” metabolic testing. In some cases, all test results are in the normal range for the laboratory, but abnormal ratios of metabolites offer clues to the diagnosis.

The identification of patients with AMD has now become routine Kennedy Krieger Institute, in part because of its specialization in both ASD and metabolic diseases and in part because of the availability of onsite biochemical testing.

Natural History of Autism with Mitochondrial Disease. The natural history of AMD and the events surrounding the period of regression are as important as the biochemical abnormalities in establishing the diagnosis. Before regression, all affected children have had normal or even advanced language and cognitive development and no neurological abnormalities apart from mildly delayed gross motor milestones and hypotonia in a few. Regression often can be dated to a specific event, most often a simple childhood illness, such as otitis media, streptococcal pharyngitis, or viral syndrome, or, rarely, an immunization, most often the MMR vaccine or the former DPT. The common feature of all identified precipitants is inflammation. Regression occurs either acutely during the illness or within 14 days of immunization with the MMR attenuated virus vaccine. Regression is otherwise typical for autism and includes acute or subacute loss of language, onset of perseverative behaviors, and loss of eye contact and other social skills. Although neurological regression in many mitochondrial diseases and other metabolic disorders often occurs because of illness-associated fasting, most children with AMD continue to eat normally during the crisis. Moreover, regression during an illness can occur whether or not there is fever. The nature of the regression and its timing suggest that mitochondrial failure is caused by immune-mediated destabilization of mitochondria as part of a TNF-alpha/caspase-mediated apoptosis cascade [5]. Because “steady state” loading of complex I in brain is close to 50% [6,7], if a child had a 50% reduction in complex I activity due to  aplo insufficiency for a complex I null mutation, just a 5 or 10% further reduction in mitochondrial activity could cause neurons to cross the threshold for energy failure and cell death. 

The well-defined role of nutritional factors in modulating the inflammatory response and the shift from animal fats to vegetable-derived fats in western diets are important factors to consider in the cause and treatment of AMD. The increase in the consumption of pro-inflammatory omega-6 fatty acids in infancy and early childhood over the last generation has been particularly striking. The established role of inflammation in causing mitochondrial destabilization [8,9] could explain an increasing incidence of regressive autism in individuals who have otherwise asymptomatic variants of complex I deficiency, which may have specific adaptive function in host defense and cognitive development [10]. In this respect, AMD, which in our experience is the cause of most regressive autism, could be another inflammatory disorder among several that have seen a markedly increased incidence over the last 20 to 30 years: asthma, inflammatory bowel disease, atopic dermatitis, eosinophilic gastroenteritis, and type I diabetes [11]. The recognition of inflammation as an apparently common cause of regression in AMD recommends the use of anti-inflammatory agents, including ibuprofen and leukotriene receptor inhibitors (i.e. montelukast, zafirlukast), to prevent further injury in children with AMD. For example, the recently reported increased risk for post-MMR autistic regression in children given pro-oxidant acetaminophen [12] could also be interpreted as an increased risk for developmental regression in those who were not given ibuprofen. Moreover, the effect of the gradual elimination of aspirin use in children between the 1980s and 1990s following the Reye syndrome epidemic 6 may have contributed to the rise in the incidence of autism, although, epidemiologically, aspirin elimination alone is not likely to be a major factor in the rising incidence of regressive autism.

  

Although most patients with AMD have a discrete episode of acute or subacute language loss and social regression, some will manifest only relative stagnation of development for a period of several months to a year or more. At least 90% of such events––developmental regression or stagnation––occur in a window of vulnerability between 12 and 30 months.

  

The goals for treatment of AMD due to complex I deficiency are:

1)    Augment residual 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)

Immediate behavioral improvement with carnitine treatment in a child with regressive autism makes complex I deficiency the most likely cause

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.

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. 

the MMR vaccine has been temporally associated, if rarely, with regression in AMD and other mitochondrial diseases when given in the second year. Doubtless some of these regressions are coincidental, since the usual age for giving the MMR falls within the typical window of vulnerability for AMD regression. In some children, however, MMR-suspected regression has coincided with the peak inflammatory response on days 8 to 10 post-immunization, as measured by IL-10 levels [28]. Unfortunately, the falling rates of immunization with MMR in the United States and other countries all but guarantees that major outbreaks of measles, mumps, and rubella will occur in the near future

Nutritional Factors Diet is another variable to consider in the treatment of AMD. Vegetable oils that are “pro-inflammatory” due to low levels of omega-3 (n-3) fatty acids and increased amounts of linoleic acid and other omega-6 (n-6) fatty acids today predominate in infant formulas and most prepared foods, largely because 13 of nutritional recommendations to avoid animal fats containing saturated fatty acids and cholesterol. The serious consequences of this trend are now being felt. A study in 2000 [29] showed that two- to four-month old breast-fed infants had more than twice the level of docosahexaenoic acid (C22:6n-3) and higher levels of most other n-3 fatty acids compared to formula-fed infants, although immunological consequences of the difference could not be demonstrated using limited immunological assays in that particular study. While the average child may suffer no obvious ill effects from diets deficient in n-3 fatty acids, the possible proinflammatory effect of these diets could be a contributing factor to infection-induced regressive autism in a child who has a metastable mitochondrial disorder. Moreover, in view of a recent study that associated decreased synthesis of cholesterol with rare cases of non-regressive autism [30], the early termination of breast-feeding and the major shift in infant diets toward low-cholesterol vegetable fats could be contributing factors to the apparent rise in the incidence of both regressive and non-regressive autism. Indeed, studies over the last two decades have shown that absence or early termination of breast-feeding is associated with higher rates of autism [31]. The simplest way to assure a adequate amount of C22:6n-3 and related fatty acids for children on typical vegetable-oil enriched diets is to provide an oil supplement, such as flaxseed oil, which is enriched in the precursors for C20 and C22 n-3 fatty acids, or salmon oils, which contain substantial amounts of DHA and EPA and a relatively low mercury content compared to many other fish species. C. Medications Certain behavior medications used in the treatment of ASD are inhibitors of complex I and, therefore, warrant consideration in treating children with AMD. Although these medications appear to have little effect on overall energy metabolism in individuals with normal mitochondria, clinically significant compromise of mitochondrial function can occur when complex I is impaired and relatively high doses of the more inhibitory drugs are prescribed. The complex I-inhibiting drugs most likely to be used in the treatment of ASD include both typical and atypical neuroleptics, such as risperidone (Risperdal), haloperidol, and some SSRIs. Although these medications are used most often in older children who are beyond the vulnerable period for autistic regression, this theoretical risk should be considered when prescribing older generation neuroleptics, such as haloperidol and related drugs, with a higher risk for development of tardive dyskinesias.

These older neuroleptics have been shown to inhibit complex I activity in direct proportion to their propensity to cause tardive dyskinesia [32]. However, there is no evidence that the newer “atypical” neuroleptics, such as risperidone and quetiapine, which have a low risk for extrapyramidal damage, are contraindicated in children with AMD and other mitochondrial diseases. Indeed one of the commonly used atypical neuroleptics, risperidone, has been shown to possibly against mitochondrial injury via modulation of damaging stress induced calcium influxes into mitochondria [33].

Novel Mitochondrial Drugs

Edison Pharmaceuticals is developing treatments for mitochondrial disease.

EPI - 743

  

EPI-743 is a drug candidate in clinical development primarily focused on inherited mitochondrial diseases. EPI-743 is administered orally, passes into the brain, and works by regulating key enzymes involved in the synthesis and regulation of energy metabolism.
Through expanded access protocols and prospective clinical trials, EPI-743 has been dosed for more than a cumulative 130,000 patient dosing days (as of November, 2013), and has recorded a favorable human safety profile. Subjects with over 15 discrete diseases have been treated. 

EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome

Genetic Dysfunctions

The prevalence of mitochondrial disorders (excluding autism) is estimated to be about 1:8500

Mitochondrial Disorders Overview

and yet it is estimated that 1 in 200 people have a defective gene linked to a mitochondrial disorder. 

Pathogenic Mitochondrial DNAMutations Are Common in the General Population

This implies a multiple hit mechanism, like we saw with cancer in an earlier post.  It also shows the potential to be misled by genetic information.  Just because the defect is there does not mean it will actually cause anything to happen, further rare events may also be needed to trigger it.

Alternatively, maybe there are far more people with a mitochondrial disease than the above studies suggest.  They are not including people with regressive autism, for one.  Something like 1 in 200 people have regressive autism.

  

What happened to Dr Richard Kelley?

If you have read the full paper by Dr Kelley you are probably wondering what else he has to say about autism.  He is an extremely rare mainstream clinician who actually does know about the subject.

You might also be wondering how come such a doctor can write about vaccination triggering mitochondrial disease and then autism, albeit in rare cases.

Perhaps this is why he does not write further about autism?

Dr.Kelley's research has focused on the elucidation of the biochemical basis of genetic disorders. Through the application of various techniques of biochemical analysis but especially mass spectrometry, Dr. Kelley has discovered the biochemical cause, and thereby the genetic etiology, of more than a dozen different diseases.

People do write about autism and mitochondrial disease, but some of these researchers are from the fringe and are not taken very seriously by the mainstream.

Carnosine for Autism – an Alternative to N-Acetylcysteine (NAC)? or is it Complementary?

Several people have mentioned to me a supplement called L-Carnosine, so I thought it was worthy of its own post.

The first thing to note is lots of supplements have very similar names and indeed two entirely different substances are abbreviated to NAC.

·        Carnosine

·        Carnitine

·        L-Carnosine

·        L-Carnitine

·        N-Acetylcysteine    (abbreviated to “NAC”)

·        N-Acetylcarnosine  (also abbreviated to “NAC”)

In this blog, and in most literature on autism, NAC refers to N-Acetylcysteine.

This post is about Carnosine and L-Carnosine, but there is also research on the use of Carnitine and L-Carnitine regarding autism and Retts syndrome.  So double check what is on the label, if you do indeed order some.

Vladimir Gulevich, Carnosine (and Carnitine)

Vladimir Gulevich  received the degree of doctor of medicine in 1896 from the department of medicine of Moscow State University. From 1900, he rejoined the Moscow State University where he was rector for a brief period of time in 1919. He was a full member of the USSR Academy of Sciences since 1929.

Gulevich discovered both Carnosine and Carnitine in his work in Moscow.  Even today his university is a centre of research for both these substances.

Carnitine and carnosine are composed of the root word carn, meaning flesh, alluding to its prevalence in animal protein. A vegetarian (especially vegan) diet is deficient in adequate carnosine, compared to levels found in a standard diet.

Researchers in Britain, South Korea, Russia and other countries have shown that carnosine has a number of antioxidant properties that may be beneficial.

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress.

Carnosine can chelate divalent metal ions.  DAN Doctors probably do not know what divalent means, but in Hg²⁺ the “2” means divalent and Hg means mercury.

Carnosine was found to inhibit diabetic nephropathy.

Carnosine-containing products are also used in topical preparations to reduce wrinkles on the skin.

Some studies have detected beneficial effects of N-acetylcarnosine in preventing and treating cataracts of the eyes.

Carnosine and Autism

Small studies, including this one by Michael Chez, have shown the benefit of L-carnosine in autism.  By the way, Chez seems to be one of the handful of genuinely knowledgeable autism clinicians anywhere on the planet.

Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders.

Abstract

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.

As Dr Chez points out, nobody is 100% certain why it is of benefit.  It could just be the anti-oxidant properties of carnosine or it could be something related to the interaction between carnosine and GABA in the brain.  GABA is an important neurotransmitter in the brain.

Other GABA related drugs show a positive effect in types of autism.  These include Baclofen, Arbaclofen, Bumetanide, Clonazepam and even Valproic acid (VPA).  The underlying mechanisms do differ, but all relate, in one way or the other, to GABA.

The Carnosine dosage used by Dr Chez was 800mg per day.

The body deploys a range of enzymes, called carnosinases, to break down carnosine.  In order to maximize the effect, and out-smart the  carnosinases, it might be wise to split the dose into two per day.

In a perfect world it might be simpler to inhibit the carnosinases and just rely on the carnosine from meat in the diet.

You cannot patent naturally occurring substances, so nobody can patent carnosine and no drug firm will therefore research it.  A carnosinase inhibitor could be patented and therefore could be made into a drug.

Carnosine and GABA

It looks like Moscow State University is still the centre of knowledge for Carnosine and Alexander A. Boldyrev recently published a book called:-

Carnosine and Oxidative Stress in Cells and Tissues

Book Description:

The main aim of this new book is to summarize the knowledge on the metabolic transformation of carnosine in excitable tissues of animals and human beings and to analyze the nature of its biological activity. At the beginning of monograph, the short history of the problem is stated. Distribution of carnosine in tissues, its appearance in ontogeny of vertebrates and correlation between carnosine content and functional activity of tissues are discussed. Chemical properties of carnosine and its natural derivatives and their ability to bind heavy metals and protons in water solution are documented. Special attention is paid to free radical quenching ability and to anti-glycating action. Biological activity of carnosine and carnosine containing compounds was tested using biological models of several levels of complexity, starting from individual enzymes and acellular mixtures and finishing to living cells and survival animals. Effects of carnosine on the whole animals under ischemic, hypoxic and other extreme conditions are described. In conclusion, the ability of carnosine to protect brain and muscular tissues from oxidative injury during exhausting exercise, extreme loading or neurodegenerative diseases is demonstrated. Based on these properties, carnosine is postulated to be a potent protector of human beings from oxidative stress.

You can preview much of the book on Google Books

We know from many autism researchers that oxidative stress is a feature of many people’s autism.  Anything that reduces this stress should have a positive effect on behaviour.

Common antioxidants used in autism include:-

·        N-Acetlycysteine (NAC)

·        Alpha Lipoic Acid (ALA)

·        All the many “chelating” substances used by DAN Doctors

Carnosine may be just an alternative anti-oxidant.

However, when you look through Boldyrev’s book, it does look possible that the chemical relationship between GABA and Carnosine many also play a role.

Conclusion

People currently taking Carnosine for Autism might well want to try N-Acetlycysteine (NAC) and see if they notice an additional benefit.  Conversely, the current NAC converts, like my son Monty, aged 11 with ASD, may well want to give Carnosine a try and see what happens.

One blog reader with Asperger’s finds Baclofen highly beneficial; he might as well give Carnosine a try, based on the GABA relationship.

Current research indicates 2,400 mg of NAC and 800 mg of Carnosine. 

It would be nice if one day somebody would do a controlled trial of NAC vs Carnosine vs Carnosine+NAC;  but don’t hold your breath.

Some people with diabetes are already taking ALA (Alpha lipoic acid) or Thioctacid for neuropathy, but find it also increases insulin sensitivity; this means they need less insulin.  They might well find both NAC and Carnosine will further increase insulin sensitivity.  Generally speaking it seems that low insulin sensitivity is bad and high insulin sensitivity is good; but I am no expert on diabetes.

In some counties Carnosine is not available, but you simply can buy it online on Amazon, ebay or many other sites. 

More on Carnosine from Harvard Medical School

Autism Flare-Ups & Leaky Blood Brain Barrier

As I discussed in an earlier post, autism flare-ups occur regularly in the lives of many autistic children.  The cause might be a pollen allergy, food allergy or indeed an illness that does not cause a fever.

That last part might sound odd, but fever actually reduces autistic behaviours.  This has been noted and documented by many, but never conclusively explained.  Lots of parents have noticed and one even created a blog about it, but they have not explained it.

To investigate the fever effect, you first need to understand thermoregulation, the process by which the body sets and maintains its temperature and the role played by of the HPA axis (hypothalamic-pituitary-adrenal axis).  The simplified explanation is that the body initiates a fever as part of its defence mechanism to the threat that has been detected, like an infection of some kind.  Certain hormones are released so as to raise and then maintain a steady higher temperature; they include TRH, ACTH, AVP, PRL and TSH. It occurred to me that if you could identify which hormone increase was behind the reduction in autistic behaviours during fever, you would be on to something really useful.  This is something that is very poorly covered in the literature and so it is very difficult to prove anything.  My hunch is that TRH is the one and I am looking into ways to prove it.  I wrote an early post all about TRH, which I believe, for other reasons could have great therapeutic value in autism. 

The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism

Back to flare ups …

 

Sickness involving stress/inflammation, but without fever, makes autistic behaviours worse.  Stress and inflammation have been shown in research to make the Blood Brain Barrier (BBB) more permeable.  In an earlier post we discovered that histamine itself increases the permeability of the BBB.

If you want to read up on the BBB, here is some heavy reading:-

The Blood-Brain Barrier/Neurovascular Unit in Health and Disease

The other observation that seems not to get documented in the literature is the effect of a new cause of stress/inflammation on any previously existing or dormant ones.  This is very relevant in autism since part of the brain is known to be in a near permanent state of inflammation/stress.  So if a new site of inflammation/stress elsewhere in the body will “re-ignite” other weak sites around the body (including the brain) then we have a problem.  Just as we showed that pollen and food allergies sparked autism flare ups, so can a viral infection.

Because there is no temperature, you may hardly notice the virus. Most parents think their kids are only really sick if they have a temperature.

These observations actually apply to all of us.  My son Monty, aged 10 with ASD, currently has a virus that does not cause a fever.  I know all about it, because I subsequently caught it from him.  Having caught it myself, I see why it would affect Monty’s behaviour.  It goes on far longer than a common cold, but outwardly after a day sneezing and a runny nose there is little to notice.  Since I am now focused on autism flare up and comorbidities, I am taking a lot of notice.  I can see that in my own body sites of previous inflammation do indeed flare up.  Like many people, I occasionally suffer from GERD, which you might know better as “heartburn”.  This causes inflammation to the oesophagus and when it occurs you can actually feel it, as I can while writing this.

Imagine you have a brain with chronic neuroinflammation, even if you are taking steps to put out that fire (NAC and statins) along comes a wave of inflammatory cytokines released elsewhere in the body and they act to reignite the inflammation in the brain again.

In healthy neurotypical people the brain is better protected from such inflammatory cytokines due to a more effective Blood Brain Barrier (BBB).  In autism there is plenty of evidence pointing to a more permeable BBB.

You cannot stop your child getting pollen allergies, though you might well adjust diet to avoid food allergies; but can you do anything to keep those pro-inflammatory cytokines out of the brain?

We know for a fact that certain substances weaken the BBB; we just need to find the neuro-protective ones that can strengthen the BBB.  Such substances do indeed exist.  A common issue than arises is that what works in the test tube (in vitro) does not always work in humans (in vivo) and also what works in rodents (the typical laboratory test subject) may not apply to humans.

Other diseases linked to leaky BBB - Multiple Sclerosis & Alzheimer’s

The best known disease long thought to be caused by a breakdown in the BBB is multiple sclerosis.  People with MS and those trying to help them have a big interest in what might protect the BBB.

I found it interesting that recent research shows that Alzheimer’s disease is also triggered by a failure in the BBB.  

Alzheimer's protein damages blood brain barrier

Alzheimer's disease: A breach in the blood–brain barrier

Alterations in brain blood vessels in mice precede the neural dysfunction associated with Alzheimer's disease. The finding highlights potential targets for drug development.

Alzheimer’s disease (AD) is well researched/funded since it is the leading cause of dementia.  It is characterised by both oxidative stress and neuroinflammation, as is autism.  Drugs developed for AD that target strengthening the BBB or reducing stress/inflammation in the brain would be good targets to trial in autism.

Substances neuro-protective to the BBB.

If you look in the literature you struggle to find much research on strengthening the BBB.  Much more frequent reference is made to “neuro-protective” ,which is something good but subtly different.

  

Mast cell stabilizers.

                         

Mast cell stabilizer drugs work to prevent allergy cells called mast cells from breaking open and releasing chemicals that help cause inflammation.

 

Commonly used mast cell stabilizers in medicine include  the drugs Cromoglicic acid and   Ketotifen.  These drugs are used in treating allergies and asthma. Both these drugs have been covered in earlier posts and at least Ketotifen is used in autism. Some researchers suggest that truly effective mast cell stabilizers for humans do not exist.  It is suggested that mast cell stabilizers would be highly protective of the BBB.

Lipoic Acid

It has been stated that Lipoic acid is protective of the BBB, also known as  Alpha lipoic acid and thioctacid; it is another antioxidant.  I have also mentioned it previously in this blog.

Thioctacid is prescribed by doctors to patients with diabetic polyneuropathy in Germany and most East European countries.  It not only reduces symptoms of neuropathy but it also reduces the amount of insulin patients require.  It is given both intravenously and orally.  I am told that oral administration is effective, but research showed that IV has the strongest effect.

In autism some people in the US take advantage of its metal-chelating properties.  All anti-oxidants have should have metal-chelating properties, by the way.

 

Here is a study from the world of Multiple Sclerosis, into the protective properties of Lipoic Acid.

Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity

In the following research NAC was combined with Lipoic Acid to reverse memory impairment and oxidative stress in the brain.

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

These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants

From Iran, I found a hypothesis about lipoic acid reducing inflammation in autism. 

Gold nanoparticles and lipoic acid as a novel anti-inflammatory treatment for autism, a hypothesis

Anti-oxidants as neuroprotectors

Anti-oxidants will indirectly strengthen the BBB, since they reduce the oxidants that damage the BBB.  Are all anti-oxidants equal?  There is an argument that you should match the anti-oxidant to the oxidant.  The most powerful anti-oxidant available seems to be NAC, and I am already using it.  My second choice would be L-carnitine, since there has been at least one positive clinical trial in autism.

A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders

It works in a quite different way to NAC and it also has an effect on the mitochondria.  As you saw above, there is also a case to be made for alpha lipoic acid (ALA), as an antioxidant.  In the research combinations of antioxidants have been trialled, just not for autism.  In an ideal world, some research would be carried out comparing the effectiveness of different combinations of NAC, Carnitine and ALA.

Interestingly as with lipoic acid, L-carnitine improves insulin response in diabetics.

I found this Alzheimer’s research interesting.  It tested NAC, carnitine and SAMe.  SAMe is used in to treat many neurological conditions, including ADHD, which I view as autism-lite.  It is also used to treat seizures, a major comorbidity of autism.

Effects ofdietary supplementation with N-acetyl cysteine, acetyl-L-carnitine andS-adenosyl methionine on cognitive performance and aggression in normal miceand mice expressing human ApoE4.

In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.

Statins

Statins are claimed to increase the integrity of the BBB.  I am already convinced of the benefit of Atorvastatin, for other reasons.

Flavonoids:  luteolin, Quercetin, Rutin

Dr Theoharides from Tufts University in Boston where he is Professor of Pharmacology, Internal Medicine (Allergy) and Biochemistry is a proponent of flavonoids to stabilize mast cells,  He favours a mix of luteolin, Quercetin, Rutin all mixed up in olive kernel oil.  He says it works far better than Ketotifen and cromolyn.  His mixture is marketed under the name Neuroprotek.

Mast stabilizers are claimed to reduce BBB permeability, so as a consequence these flavonoids should help

I initially found it odd that such a scientist was favouring natural extracts,  so I thought I would see what other neuro-protective extracts might be out there.

Naturally occurring neuro-protectants

The internet is full of natural remedies and most have little supporting evidence.  Here are two that I found interesting.

Blueberries

These are both very tasty, available and remarkably good for you; nobody is exactly sure why.  They seem to slow down cognitive decline in older people, reduce neuroinflammation and promote cell survival.

Antioxidant and neuroprotective properties of blueberry polyphenols: a critical review

Over the last 10 years an increasing scientific interest has developed about polyphenols, which are very abundant in blueberries, as they have been seen to produce favourable effects related to neuroprotection and linked to a possible decrease of age-related cognitive and motor decline, as shown by the improvement of such functions in animal models with a supplemented diet. Such effects could not only be explained through a purely antioxidant action but also through more complex mechanisms related to inflammation, genic expression, and regulation of cell survival

Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection.

Withania Somnifera, also known as Ashwagandha

On the surface, this ages old Indian medical remedy looks interesting, not least because one study showed it could reverse Alzheimer’s Disease.  It is claimed to do many things, including protecting the BBB.

Withania somnifera reverses Alzheimer's disease pathology

Indeed it is an ingredient used in some supplements used for autism and if you Google it, you will parents recommending it.

Not being a regular to such types of “medicine” I did some research and found that you should buy the actual root rather than the ground up bits available in capsules.  The logic being that they put the leftovers in the capsules and that the capsules may give an overly concentrated dose, as compared to the tea version. 

With root you make a kind of herbal tea.  It is actually very easy and quite inexpensive; indeed the root seems easier to find than the capsules.  In keeping with my self-experimentation approach, I brewed up a batch of Withania somnifera tea and gave it a try.  Well there genuinely is an effect; you do feel different, although I would not call it “better”.  The problem is, as I learnt a couple of hours later, that it can, and does, irritate the gastrointestinal tract.  Maybe my brew was too strong or maybe I am just sensitive to it.  On WEBMD they list the following side effects:-

ASHWAGANDHA Side Effects & Safety

Ashwagandha is POSSIBLY SAFE when taken by mouth short-term. The long-term safety of ashwagandha is not known. Large doses of ashwagandha might cause stomach upset, diarrhoea, and vomiting.

It’s not known whether it’s safe to apply ashwagandha directly to the skin.

Special Precautions & Warnings:

Pregnancy and breast-feeding: Do not use ashwagandha if you are pregnant. It is rated LIKELY UNSAFE during pregnancy. There is some evidence that ashwagandha might cause miscarriages. Not enough is known about the use of ashwagandha during breast-feeding. Stay on the safe side and avoid use.

Stomach ulcers: Ashwagandha can irritate the gastrointestinal (GI) tract. Don’t use ashwagandha if you have a stomach ulcer.

“Auto-immune diseases” such as multiple sclerosis (MS), lupus (systemic lupus erythematosus, SLE), rheumatoid arthritis (RA), or other conditions: Ashwagandha might cause the immune system to become more active, and this could increase the symptoms of auto-immune diseases. If you have one of these conditions, it’s best to avoid using ashwagandha.

Surgery: Ashwagandha may slow down the central nervous system. Healthcare providers worry that anaesthesia and other medications during and after surgery might increase this effect. Stop taking ashwagandha at least 2 weeks before a scheduled surgery.

Since Ashwagandha can make the immune system more active, it would seem unsuitable for autism, which we have established in this blog is linked to an already overactive immune system.

Conclusion

Finding a remedy to permeability of the blood brain barrier (BBB), was never going to be simple, if it was, then multiple sclerosis and Alzheimer’s disease would have already  become curable.  But, knowing what weakens the BBB does help explain why autism flare-ups occur, and in turns this helps us to minimize them.

I think I will stick with the blueberries and steer clear of the Ashwagandha, at least until I have to worry about Alzheimer’s.  The L-carnitine is getting a trial as a supplemental anti-oxidant and mitochondria protector, as will Dr Theoharides’ somewhat expensive Neuroprotek.  Alpha lipoic acid is now in third position in my anti-oxidant league table and will be studied further.   NAC remains in pole position as antioxidant proven to reduce autistic behaviours.  The very inexpensive Ketotifen may have capabilities above and beyond those accepted by Theoharides, as suggested by the fact that it has the remarkable ability to prevent the onset of asthma in the at risk group.

I wrote an earlier post on flavonoids.  These are good parts of fruits that you usually miss out on in juices, since they are concentrated in the skins.  Indeed though olive oil contains beneficial flavonoids, many remain in the stone/kernel in the centre,  It was of interest to me that Theoharides uses olive kernel oil rather than regular olive oil to bind his Neuroprotek together.  All berries seem to be particularly good for you, including cranberries, blackberries, blueberries, billberries and raspberries. I think these flavonoids are likely more about promoting your general health than any autism breakthrough.