Cerebral Folate Deficiency – increasing cerebral folate without increasing plasma/blood folate, via activating the reduced folate carrier (RFC)

 

Source: https://autism.fratnow.com/blog/folate-transport-systems-i-transmembrane-carriers/

Two readers of this blog have been telling me about the fundamental role of brain energy and metabolism in autism. Marco sent me a book called Brain Energy by a psychiatrist at the Harvard Medical School. He stumbled upon this subject when he encouraged a patient to lose weight using the ketogenic diet. As well as losing weight, the patient’s decades-long psychiatric disorders seemed to vanish. The author, Dr Palmer, now believes that many of his patients actually have metabolic disorders as the underlying basis of their psychiatric symptoms. 

Our reader Natasa is approaching with a similar idea, essentially that autism features a brain running on empty.

Today’s post is about increasing the level of folate within the brain, by targeting similar metabolic pathways to those that will boost “brain energy.”

Low levels of folate within the brain will cause varying degrees of neurological disorder.

There are three ways folate can cross into the brain.

1.     Folate receptor alpha (FRA)

2.     Proton-coupled folate transporter (PCFT)

3.     Reduced folate carrier (RFC)

Autoantibodies to the FRA have been linked to neurodevelopmental diseases, particularly cerebral folate deficiency, schizophrenia and autism. Recent studies have shown that these neurodevelopmental disorders can be treated with folinic acid (leucovorin).

Dr Frye, Professor Ramaekers and others are targeting the problem of low folate in the brain by supercharging the level of folate in the bloodstream and hoping more squeezes through the blood brain barrier.

In my previous post I mentioned that Agnieszka has pointed out the idea of using the supplement PQQ. This targets the third transport mechanism above, it is aiming to get more folate across via  the Reduced Folate Carrier (RFC).

Somebody recently wrote their PhD thesis on exactly this topic:- 

Regulation of Folate Transport at the Blood-Brain Barrier: A Novel Strategy for the Treatment of Childhood Neurological Disorders Associated with Cerebral Folate Deficiency

Camille Alam, Department of Pharmaceutical Sciences, University of Toronto 

Additionally, we provided in vitro and in vivo evidence that RFC expression and transport activity is inducible by another transcription factor, NRF-1. These findings demonstrate that augmenting RFC functional expression through interaction with specific transcription factors could constitute a novel strategy for enhancing brain folate delivery. Modulating folate uptake at the BBB may have clinical significance due to the lack of established optimal therapy for neurometabolic disorders caused by loss of FRα or PCFT function. 

What Camille is saying is that if folate transport mechanism number 1 and/or number 2 are not working, we can reinvigorate mechanism number 3.

So if you have Dr Frye’s folate receptor antibodies, or PCFT isn’t working then you might focus on Reduced Folate Carrier (RFC).

The good news is that we have lots of ways to target Reduced Folate Carrier (RFC).

We do not, it seems, have any clever ways to target PCFT. 

NRF-1 and PGC1-alpha

There is a lot in this blog about PGC1-alpha, because it is the master regulator for biogenesis of mitochondria.

All those people with impaired “brain energy” would love to activate PGC1-alpha.

NRF-1 is an activator of mitochondrial respiratory chain genes. NRF-1 specifically targets genes encoding subunits of the mitochondrial respiratory chain complexes, particularly complexes I, III, and IV. By binding to their promoters, NRF-1 directly stimulates their transcription, leading to increased synthesis of these critical protein components and enhanced oxidative phosphorylation (OXPHOS) capacity.

Synergy between NRF-1 and PGC-1alpha

PGC-1alpha acts as the upstream regulator. Various stimuli, such as exercise, cold exposure, and certain hormones, can trigger PGC-1alpha expression. Once activated, PGC-1alpha directly interacts with and co-activates NRF-1, enhancing its binding to target gene promoters and amplifying its transcriptional activity.

NRF-1 as the downstream effector.  NRF-1 fine-tunes the expression of specific mitochondrial genes, ensuring a balanced and efficient OXPHOS system. This synergy between PGC-1alpha and NRF-1 optimizes mitochondrial function and cellular energy production.

So for Natasa, trying to boost energy production in the brain and in the rest of the body, it would be ideal to have more NRF-1 and more PGC-1alpha

What has optimized mitochondrial function got to do with more folate in the brain?

It turns out that you can increase expression of Reduced Folate Carrier (RFC) via activating NRF-1 and/or PGC1alpha.

So what is good for your brain energy is likely to also be good for your brain folate.

Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier

Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems results in suboptimal folate levels in the cerebrospinal fluid (CSF) causing childhood neurological disorders. Our group has reported that upregulation of RFC at the blood-brain barrier (BBB) through interactions with specific transcription factors, that is, vitamin D receptor (VDR) could increase brain folate delivery. This study investigates the role of nuclear respiratory factor 1 (NRF-1) in the regulation of RFC at the BBB. Activation of NRF-1/PGC-1α signaling through treatment with its specific ligand, pyrroloquinoline quinone (PQQ), significantly induced RFC expression and transport activity in hCMEC/D3 cells. In contrast, transfection with NRF-1 or PGC-1α targeting siRNA downregulated RFC functional expression in the same cell system. Applying chromatin immunoprecipitation (ChIP) assay, we further demonstrated that PQQ treatment increased NRF-1 binding to putative NRF-1 binding sites within the SLC19A1 promoter, which encodes for RFC. Additionally, in vivo treatment of wild type mice with PQQ-induced RFC expression in isolated mouse brain capillaries. Together, these findings demonstrate that NRF-1/PGC-1α activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.

The hugely simple intervention mentioned above is to just take vitamin D. This has nothing to do with brain energy.

Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha

Folates are critical for brain development and function. Abnormalities in brain folate transport have been implicated in a number of childhood neurodevelopmental disorders, including cerebral folate deficiency syndrome, hereditary folate malabsorption, and autism spectrum disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. In this study, we demonstrate that functional expression of the folate transporter, reduced folate carrier, at the blood–brain barrier and its upregulation by the vitamin D nuclear receptor can remarkably increase folate transport to the brain. These findings provide a strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by folate transport defects.

 Low vitamin D correlates with poor health, dementia, and death from all causes

Taking vitamin D has become popular in recent years.

A correlation does not guarantee causality.  It was thought that vitamin D might be the silver bullet to improved health in older people. It has not proved to be.

Low vitamin D also correlates with less time outdoors, doing some physical activity. Taking vitamin D does not mean you will live longer, but we know for sure that exercise improves many medical concerns that will improve healthy life expectancy.

The concern many people now have regarding skin cancer leads to some healthy active people having low vitamin D. Put on that sunscreen and your exposed skin will not be able to produce your vitamin D.

Vitamin D is important to health and is easy to maintain in the normal range, but it is just one element of good health. It might be one way to increase folate in the brain, for those who need it. 

 

Conclusion

How do you increase folate in the brain?

The obvious way is to put more folate in your blood, this is the standard therapy. You either take calcium folinate tablets or, very rarely, the more potent infusions.

If you have antibodies blocking transport via FRA, you could follow the hypothesis that these antibodies are from a reaction to cow’s milk and try going dairy-free. There is a complex relationship between milk and folate receptor alpha antibodies (FRAA), but direct evidence of milk causing FRAA production is limited.

Milk, particularly cow's milk, contains proteins similar to folate receptor alpha found in humans. Some individuals, mainly those with a genetic predisposition, could develop FRAA that cross-react with these milk proteins. This cross-reactivity would not necessarily mean the milk directly caused FRAA production but might trigger an existing immune response. Some studies, though not all, have found an association between higher milk consumption and increased FRAA levels.

If you want to increase folate transport via our third mechanism, Reduced Folate Carrier (RFC) you have many options:

The obvious first step is to take a vitamin D supplement to raise levels to the high end of normal. This can be done by taking a larger supplement just once a week, because vitamin D has a long half-life.

As you can see from the study below in children there is a correlation between low vitamin D and low folate in children.

 

Evaluation of correlation between vitamin D with vitamin B₁₂ and folate in children

The present study reported a positive correlation between vitamin D and vitamin B12 and folate levels. Regular measurement of these two micronutrient levels in children with vitamin D deficiency is important for public health.

Vitamin D is low in much of the population, even more so in wintertime. It seems particularly low in children with autism, perhaps because they are spending less time playing outside than other children.

Activate NRF-1 and/or PGC1alpha:

1.     Exercise, particularly endurance training

2.     PQQ supplement

3.     Perhaps resveratrol/pterostilbene

4.     Butyric acid / sodium butyrate

5.     The very safe old drug Metformin

6.     Other type 2 diabetes drugs like Pioglitazone

Metformin has been shown to raise IQ in Fragile-X by about 10 points and has a range of metabolic benefits and even cancer preventative effects. This common diabetes medication primarily targets AMPK, an energy sensor molecule upstream of PGC-1alpha. By activating AMPK, metformin indirectly stimulates PGC-1alpha and subsequently NRF1, leading to enhanced mitochondrial function.

Pioglitazone has been researched in autism and is my choice for peak risk spring/summer aggression and self-injury. Pioglitazone can potentially upregulate PGC-1alpha expression through several pathways:

•                    Pioglitazone activates AMPK, an important energy sensor molecule. AMPK can then stimulate PGC-1alpha expression through various signaling pathways.

•                    Pioglitazone activates PPAR-gamma and PPAR-gamma directly interacts with PGC-1alpha, potentially increasing its activity.

I think Metformin has a better safety profile than Pioglitazone and so better for every day use.

Butyric acid does have the potential to activate PGC-1alpha. Butyric acid is produced in the gut by fermentation. You need “good” bacteria and fiber. People with healthy diet naturally produce it. You can also buy it as a supplement (sodium butyrate) since it has numerous benefits – everything from gut health, bone health to a tight blood brain barrier.

According to a doctor I was talking to recently, nobody wants to hear that exercise is a key part of health. It is free and the side effects are generally all good ones. Endurance exercise will boost NRF1 and PGC1alpha. Many people with autism are overweight, often due to the psychiatric drugs they have been put on.

Sirtuin activators boost NRF1 and PGC1 alpha. There are drugs and foods which can do this, but a potent way is through exercise.

I hope Dr Frye is checking his patients’ vitamin D levels and supplementing to the safe upper limit.

Those taking I/V calcium folinate might want to look at the more potent ways to activate NRF1 and/or PGC1alpha.

 

Mutations in CACNA2D1 plus KDM6B -- Gabapentin and Calcium Folinate? Perhaps PQQ? Perhaps BHB?

 

A little research can sometimes be eye opening

I was recently sent genetic results from several parents and surprisingly some have multiple potentially highly causal genes. Some are mutations that are extremely rare and one was unique.

Today I am looking at one case with two genes highlighted in whole exome sequencing (WES), one is a calcium ion channel and the other is a gene extremely close to the one causing Kabuki syndrome.  Interestingly, two possible interventions did very quickly appear.

The report states:

UNCLEAR RESULT

Variants of uncertain significance (VUS) identified

Based on current evidence, the clinical relevance of the detected variants remains unclear.

Kabuki syndrome is caused by mutations in KMT2D or KDM6A.

KDM6A and today’s gene KDM6B both target trimethylation on lysine 27 of histone H3 (H3K27me3), a mark associated with gene silencing. By removing this mark, they activate gene expression. So, mutations in either gene will cause a cascade of effects on numerous other genes.

The old post below suggested the use of HDAC inhibitors to correct the mis expressed genes. In particular, BHB from the ketogenic diet was discussed.

Notably, histone deacetylase inhibition rescued structural and functional brain deficits in a mouse model of Kabuki syndrome.

 

Ketones and Autism Part 5 - BHB, Histone Acetylation Modification, BDNF Expression, PKA, PKB/Akt, Microglial Ramification, Depression and Kabuki Syndrome

           

The calcium channel involved today is not one we have previously looked at, but it is the target of the very well-known drug Gabapentin. This drug is used to treat epilepsy and neuropathic pain. The child does have abnormal EEG and seizures, plus autism, ADHD and absent speech.

Mutations of the KDM6B causing autism were first described only in 2019. In 2022 mutations in this gene were found in several patients with cerebral folate deficiency (CFD), one of the authors is our old friend Dr Ramaekers.

We know a lot about CFD, thanks to our reader Roger, Dr Frye, Dr Ramaekers, and now Agnieszka and Stephen. Over in the US one of the founders of an autism organisation told me her son was diagnosed in adulthood with CFD, when he finally had a spinal tap.

Interestingly, Agnieszka has pointed out a novel way to potentially increase folate in the brain using an OTC supplement called PQQ.

 

Protective effects of pyrroloquinoline quinone in brain folate deficiency

Results

Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells. PQQ treatment was able to reverse these changes, while increasing RFC expression through activation of the PGC-1α/NRF-1 signaling pathway.

Conclusion

These results demonstrate the effects of brain folate deficiency, which may contribute to the neurological deficits commonly seen in disorders of CFD. PQQ may represent a novel treatment strategy for disorders associated with CFD, as it can increase folate uptake, while in parallel reversing many abnormalities that arise with brain folate deficiency.

 

PQQ is a relatively common OTC supplement that looks helpful in older people and those with mitochondrial dysfunctions (most older people, plus many with autism).  It can also improve sleep.  The common 20mg dose seems to be based on what was used in a clinical trial in Japanese adults. Japanese drugs are dosed to reflect the size of Japanese people. American women on average weigh 40% more than Japanese women.

PQQ is present in mother’s milk, so it is not some scary artificial compound.

CFD looks like another nexus point where may different genetic variants produce a downstream meeting point.  This means numerous different underlying autisms will share a common beneficial therapy. It will not be a cure, but it should improve the outcome.

The only way to access I/V calcium folinate looks to be via confirmation of very low levels in spinal fluid, so a spinal tap would be necessary.  This is not easy, as Agnieszka has found out.  For some people oral calcium folinate is not sufficiently potent to reverse CFD.

KDM6B

Mutations of the KDM6B gene causing autism were first described only in 2019. In 2022 mutations in this gene were found in several patients with cerebral folate deficiency (CFD).

 

Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features

Lysine-specific demethylase 6B KDM6B demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

 

Layman’s guide to the KDM6B gene

https://www.simonssearchlight.org/research/what-we-study/kdm6b/

 

12% of people with CFD studied in the paper below had mutations in KDM6B. So clearly all people with a mutation in this gene should be tested for CFD vis a spinal tap.

 

KDM6B Variants May Contribute to the Pathophysiology of Human Cerebral Folate Deficiency

Cerebral folate deficiency syndrome (CFD) was defined as any neurological condition that was associated with low concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid. Previous clinical studies have suggested that mutations in the folate receptor alpha FOLR1 gene contribute to CFD. In this study, we identified six genetic variants in histone lysine demethylase 6B (KDM6B) in 48 CFD cases. We demonstrated that these KDM6B variants decreased FOLR1 protein expression by manipulating epigenetic markers regulating chromatin organization and gene expression. In addition, FOLR1 autoantibodies were identified in CFD patients’ serum. To the best of our knowledge, this is the first study to report that KDM6B may be a novel CFD candidate gene in humans.

The way to confirm CFD, with certainty, is via a spinal tap.  This can then open the door to intravenous therapy with calcium folinate.

There is a blood test which then would lead to oral calcium folinate therapy.  This is now very common in children with autism in the US. It improves speech.

www.fratnow.com

The problem is that some people need the more potent intravenous therapy and without a spinal tap there is not enough proof to get the therapy.

 

CACNA2D1

The CACNA2D1 gene encodes voltage-dependent calcium channel subunit alpha-2/delta-1. 

Different types of mutation will have different effects and varying degrees of severity.

Some mutations in this gene are associated with a condition called “Developmental and Epileptic Encephalopathy 110”.

Developmental and epileptic encephalopathy-110 (DEE110) is an autosomal recessive disorder characterized by profound global developmental delay and hypotonia apparent in infancy followed by onset of seizures in the first months or years of life. Affected individuals achieve almost no developmental milestones and show impaired intellectual development, poor or absent speech, inability to walk or grasp objects, peripheral spasticity, and poor eye contact. Brain imaging shows hypoplastic corpus callosum and cortical atrophy.

CACNA2D1 is also a novel Brugada Syndrome susceptibility gene.

Brugada syndrome may be a major cause of sudden cardiac death in men under 40. People with Brugada syndrome on average die between the ages of 26 to 56 years, with an average age of 40 years. If treated appropriately, patients can have a normal lifespan.

A pediatric cardiologist should be consulted.

Fortunately the Alpha-2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain.

This means that an obvious path to investigate is whether the drug gabapentin has a positive effect. Mutations could produce either gain of function of loss of function.

Gabapentin binds to a the α2δ subunit. This binding does not directly block or open the channel, but it influences its overall activity.

The exact mechanism of action is still not fully understood, but it is believed that gabapentin:

·       Reduces the release of certain neurotransmitters involved in pain signaling, such as glutamate and substance P.

·       Alters the trafficking and function of the calcium channels themselves.

·       Therefore, gabapentin's action is more complex than simply "blocking" or "opening" channels. 

Gabapentin is not guaranteed to help in this case, but certainly might do.

Conclusion

The take home is really that if you invest thousands of dollars/euros/pounds in genetic testing, it is well worth your time spending some time on the internet looking up any flagged genes.

People expect too much from the geneticist writing the report.

Double check these things yourself.  Take your findings to an open-minded neurologist, who reads the research literature.

Be aware that the same mutation can be present in one or even both parents, with no noticeable negative effect, but be disease causing in their child. Genetics is often about the probability of something happening, rather the certainty. 

Look at partially-effective or sometimes-effective interventions in the research. For example, one reader is looking at mutations in NF1 plus a gene affecting epigenetics. He might want to try Lovastatin.  NF1 causes an increase in RAS, which is a pro-growth signal, this leads to RASopathies which can cause intellectual disability (ID). Lovastatin reduces RAS and it was trialled to reduce ID in NF1 - the results were mixed. It probably matters at what age you start trying to reduce RAS.

Walnuts for Brain Health in Aging and ADHD, but in Autism?

 

Source: Ivar Leidus - Own work, CC BY-SA 4.0,  https://commons.wikimedia.org/w/index.php?curid=98723321

 

Diet does seem to be the most popular intervention for autism and it does appear to give benefits, particularly in those with milder autism.

There are lessons to be learnt from healthy aging, when looking at how to optimise brain function in those with a neurodevelopmental disorder like autism.

As we age, multiple processes in the body start to function sub-optimally and this pretty much determines our healthy life expectancy. There are overlaps between features of this sub-optimal function (oxidative stress, mitochondrial dysfunction, neuroinflammation etc) and what is present in people with level 3 autism and/or intellectual disability.

The dietary keys to healthy aging:

A healthy varied diet rich in fruits, berries, vegetables, whole grains, legumes and nuts.

Healthy fats and lean protein.

To this we have to add all those herbs and spices.

Herbs, in large quantities, are a key element of the Mediterranean diet and are often omitted by people trying to copy this diet. I still remember meeting our reader Petra in Greece and receiving her gift of olive oil and oregano – it was a huge bag of oregano, not the size you might find in a supermarket in Northern Europe.

The healthy Okinawa diet is distinguished by low-calorie intake, fish, very little meat, fermented food (like natto), not to forget the seaweed. They also consume large amounts of a purple sweet potato. Okinawan sweet potatoes, also known as purple sweet potatoes, are a type of sweet potato that is native to Okinawa. They are characterized by their deep purple flesh, which is due to the presence of anthocyanins, a type of antioxidant.

I have to say that having visited an island in the Okinawa archipelago they also have some very unhealthy food adopted from US military bases. Spam sushi was everywhere, as are US style fast food outlets, with over-sized burgers. I found it hard going eating fish three times a day, albeit those small amounts.

 

Greece is no different, there are older Greeks with healthy traditional diets, but no shortage of giros and souvlaki joints catering to the locals and the tourists alike.

 

 

Nuts!  Not just at Christmas

Nuts are on the list of healthy foods, but I think most people neglect them.

It is difficult to incorporate sufficient nuts into your diet unless you are going to spend time eating them by the handful.

Incorporating large amounts of herbs like oregano, basil, sage, rosemary, thyme, parsley, mint etc is not so hard and you end up with much tastier food. They provide numerous health benefits. 

I was very surprised to find that there was so much evidence to support the humble walnut.

I was also surprised where some of the evidence comes from.

I did exchange emails many years ago with Abha Chauhan, a well-known researcher at the Institute for Basic Research in Developmental Disabilities in New York. She has written some very cutting edge research about oxidative stress.

She turns out to be a fan of walnuts.

She does actually list nutrition among her research interests:-

Alzheimer's disease, amyloid, free radicals, glutathione, mitochondria, nutrition, oxidative stress, protein kinases

 Her paper is here:-

Beneficial Effects of Walnuts on Cognition and Brain Health

I did previously wonder why New York has a research center into intellectual disabilities. Here is some information.

 

The Institute for Basic Research in Developmental Disabilities (IBR) is a proud part of New York State’s long history of caring for its citizens with developmental disabilities. It was in the 1940s and 1950s that the idea of creating an institute dedicated to studies in mental retardation was first discussed. In 1958, enabling legislation was passed for the creation of the Institute for Research in Mental Retardation within the New York State Department of Mental Hygiene. Ground was broken for the Institute’s research tower in 1964, and when its first laboratories opened in 1968, IBR was the first large-scale institute in the world with the mandate to conduct basic and clinical research into the causes of mental retardation. IBR became part of OPWDD, then known as the New York State Office of Mental Retardation and Developmental Disabilities (OMRDD) in 1979; a year later, it was renamed the Institute for Basic Research in Developmental Disabilities to reflect OMRDD’s broader focus on many developmental disabilities.  

Research is always good, but what really matters is translating it to therapy. How about actually getting kids with autism treated for oxidative stress? This I recall discussing with Abha and her response was that the funding is lacking for clinical trials. My response was that she could always give Mike Bloomberg a call.  How much money do you really need? 

Abha, Alzheimer’s and the walnut

As we saw Alzheimer’s was number one on Abha’s research interests. Here we have her paper suggesting walnuts for Alzheimer’s.

 

Benefits of a diet with walnuts in Alzheimer’s disease

Alzheimer’s disease is a severe neurodegenerative disorder, responsible for 60-70% of cases of dementia. The most common symptoms are memory loss, disorientation and loss of cognition. To date, there is no known cure for this disease, but Dr Abha Chauhan, based at the New York State Institute for Basic Research in Developmental Disabilities, New York, USA, has shown how supplementation with walnuts in the diet can help Alzheimer’s mice slow down the development of the disease. Her research demonstrates that walnuts can limit the oxidative stress characteristic of this condition, as well as promote the body’s natural antioxidant defence mechanisms. 

Based on these results, it’s reasonable to suggest that supplementation with walnuts may help in reducing the risk of developing Alzheimer’s disease, delaying its onset and/or slowing its progression due to the antioxidant and anti-inflammatory effects of different components of walnuts. At the very least, these results indicate that it may be worth conducting similar studies in humans.

 

It’s difficult to say at this stage what exactly in the walnut is responsible for these benefits, but in addition to antioxidants in walnuts, ALA (omega-3 fatty acid) may also be a contributing factor. While most nuts contain monounsaturated fats, only walnuts consist primarily of polyunsaturated fat, of which ALA is the main constituent. This fatty acid is the precursor of vital fatty acids, important for regulating serotonin and dopamine concentrations, as well as modulating key inflammatory and immune functions.

 

Beneficial Effects of Walnuts on Cognition and Brain Health

Oxidative stress and neuroinflammation have important roles in the aging process, mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other brain disorders. Amyloid beta protein (Aβ) is the main component of amyloid plaques in the brains of people with AD. Several studies suggest that Aβ increases the generation of free radicals in neurons, which leads to oxidative damage and cell death. Aβ can also induce neuroinflammation by increasing pro-inflammatory cytokines and enzymes. Walnuts contain several components that have antioxidant and anti-inflammatory effects. Animal and human studies from our and other groups suggest that supplementation with walnuts in the diet may improve cognition and reduce the risk and/or progression of MCI and AD. In the transgenic AD mouse model (AD-tg), we have reported the beneficial effects of a diet with walnuts on memory, learning, motor coordination, anxiety, and locomotor activity. Human clinical trials have also suggested an association of walnut consumption with better cognitive performance and improvement in memory when compared to baseline in adults. Our recent study in AD-tg mice has shown that a walnut-enriched diet significantly improves antioxidant defense and decreases free radicals’ levels, lipid peroxidation, and protein oxidation when compared to a control diet without walnuts. These findings suggest that a diet with walnuts can reduce oxidative stress by decreasing the generation of free radicals and by boosting antioxidant defense, thus resulting in decreased oxidative damage to lipids and proteins. An in vitro study with synthetic Aβ showed that walnut extract can inhibit Aβ fibrillization and solubilize the preformed Aβ fibrils, suggesting an anti-amyloidogenic property of walnuts. Because it takes many years for cognitive impairment and dementia to develop, we suggest that early and long-term dietary supplementation with walnuts may help to maintain cognitive functions and may reduce the risk of developing, or delay the onset and/or slow the progression of, MCI and dementia by decreasing Aβ fibrillization, reducing oxidative damage, increasing antioxidant defense, and decreasing neuroinflammation. Furthermore, several animal and human studies have suggested that walnuts may also decrease the risk or progression of other brain disorders such as Parkinson’s disease, stroke, and depression, as well as of cardiovascular disease and type 2 diabetes. Together, these reports suggest the benefits of a walnut-enriched diet in brain disorders and in other chronic diseases, due to the additive or synergistic effects of walnut components for protection against oxidative stress and inflammation in these diseases.

  

Walnuts for teenagers? 

That’s Nuts! Eating Walnuts Regularly Improves Cognitive Development and Psychological Maturation in Teens

Summary: Teens who added walnuts to their diet for 100 days showed improvements in attention function, and for those with ADHD, frequent walnut consumption was associated with improvements in behavior. Researchers also noted an increase in fluid intelligence in those who frequently consumed walnuts as part of their daily diet.

  

Walnuts May Help Teens with Maturity, Thinking, and Attention

 

Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial

Background

Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear.

Methods

We conducted a 6-month multi-school-based randomised controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioural development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11–16 years were randomised into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioural (socio-emotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomisation prognostic factors (including adherence) using generalised estimating equations.

Findings

In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p < 0.0001). The per-protocol (adherence-adjusted) effect on improvement in attention score (hit reaction time variability) was −11.26 ms (95% CI = −19.92, −2.60; p = 0.011) for the intervention group as compared to the control group, improvement in fluid intelligence score was 1.78 (95% CI = 0.90, 2.67; p < 0.0001), and reduction of ADHD symptom score was −2.18 (95% CI = −3.70, −0.67; p = 0.0050).

Interpretation

Our study suggested that being prescribed eating walnuts for 6 months did not improve the neuropsychological function of healthy adolescents. However, improved sustained attention, fluid intelligence, and ADHD symptoms were observed in participants who better complied with the walnut intervention. This study provides a foundation for further clinical and epidemiological research on the effect of walnuts and ALA on neurodevelopment in adolescents.  

Walnuts for Autism? 

I did find a case study from the Middle East putting forward reasons why walnuts and pumpkin may benefit some types of autism.  It was not a robust study, but I was surprised to find anything at all on this subject. 

Effects of Walnut and Pumpkin on Selective Neurophenotypes of Autism Spectrum Disorders: A Case Study

Special diets or nutritional supplements are regularly given to treat children with autism spectrum disorder (ASD). The increased consumption of particular foods has been demonstrated in numerous trials to lessen autism-related symptoms and comorbidities. A case study on a boy with moderate autism who significantly improved after three years of following a healthy diet consisting of pumpkin and walnuts was examined in this review in connection to a few different neurophenotypes of ASD. We are able to suggest that a diet high in pumpkin and walnuts was useful in improving the clinical presentation of the ASD case evaluated by reducing oxidative stress, neuroinflammation, glutamate excitotoxicity, mitochondrial dysfunction, and altered gut microbiota, all of which are etiological variables. Using illustrated figures, a full description of the ways by which a diet high in pumpkin and nuts could assist the included case is offered.

This case study does not support broad food treatments as a treatment for ASD, but it does imply that specialized dietary interventions over time may play a role in the management of certain ASD symptoms, functions, and clinical domains. The pumpkin/walnut healthy diet improved nutritional status, presumably increasing the brain’s ability to function and learn by reducing oxidative stress, neuroinflammation, glutamate excitotoxicity, mitochondrial dysfunction, and altered gut microbiota, all of which are etiological mechanisms behind the clinical presentation of ASD.   

Impact of Nut Consumption on Cognition across the Lifespan 

Cognitive health is a life-long concern affected by modifiable risk factors, including lifestyle choices, such as dietary intake, with serious implications for quality of life, morbidity, and mortality worldwide. In addition, nuts are a nutrient-dense food that contain a number of potentially neuroprotective components, including monounsaturated and polyunsaturated fatty acids, fiber, B-vitamins, non-sodium minerals, and highly bioactive polyphenols. However, increased nut consumption relates to a lower cardiovascular risk and a lower burden of cardiovascular risk factors that are shared with neurodegenerative disorders, which is why nuts have been hypothesized to be beneficial for brain health. The present narrative review discusses up-to-date epidemiological, clinical trial, and mechanistic evidence of the effect of exposure to nuts on cognitive performance. While limited and inconclusive, available evidence suggests a possible role for nuts in the maintenance of cognitive health and prevention of cognitive decline in individuals across the lifespan, particularly in older adults and those at higher risk. Walnuts, as a rich source of the plant-based polyunsaturated omega-3 fatty acid alpha-linolenic acid, are the nut type most promising for cognitive health. Given the limited definitive evidence available to date, especially regarding cognitive health biomarkers and hard outcomes, future studies are needed to better elucidate the impact of nuts on the maintenance of cognitive health, as well as the prevention and management of cognitive decline and dementia, including Alzheimer disease.

   

Conclusion

We are told in dietary advice from public health authorities that we should include nuts in our daily diet. The suggested daily amount is about 30 grams (1 ounce).

If you had to choose one nut, it looks like the walnut is the one most likely to help the brain.

Teenagers with ADHD are suggested to benefit in the research from Spain.

Abha Chauhan over in New York is a proponent of walnuts for potentially slowing down Alzheimer’s disease.

Whether walnuts may benefit some with autism is an open question, but there are reasons to believe that it should. Over in Abu Dhabi one autism practitioner is suggesting combining walnuts with pumpkin for optimal effect. 

Ensuring healthy aging with diet and exercise is actually very straight forward, but most people still choose not to do it.

Treating severe autism is much more hit and miss, but many of those who persevere see good results.