Introduction

What is folate, and why is it important for the brain?

Folate, sometimes referred to as folic acid depending on the form, is an important nutrient from the vitamin B9 family.¹ It’s not naturally made in the body and thus has to be obtained from food sources such as eggs, leafy green vegetables, legumes, poultry and fortified foods. These vitamins are essential for the body as they are necessary for many metabolic reactions that are needed for processes such as energy production, cell replication and growth, DNA repair, synthesis and many more.¹ Folate is essential for fetal development within pregnancy, with deficiencies being linked to developmental abnormalities and autism spectrum disorder.²

What is the blood-brain barrier (BBB)?

The blood-brain barrier (BBB) is a layer of epithelial cells that separates the brain from the blood transport system (e.g your blood vessels), essentially acting as a barrier. Its main role is to support the movement of important small molecules to the brain. It’s therefore responsible for the nutritional health of the brain and facilitates the transport of nutrients that can’t be delivered through the blood directly.³ It’s highly selective and prevents toxins, pathogens and other harmful components of the blood from entering the brain.⁵

As it’s responsible for the uptake of nutrients, it’s also the means by which folate is delivered to the brain. Folate is found in high concentrations in the cerebrospinal fluid and is transported across the BBB using energy as required.³ 

What is cerebral folate deficiency (CFD)?

Cerebral folate deficiency (CPD) is a neurological syndrome that’s associated with lower-than-normal levels of active folate in the cerebrospinal fluid. This is in addition to normal levels of folate outside of the nervous system. The clinical presentation of the syndrome is highly variable, thus symptoms also vary. These symptoms typically manifest during younger ages, such as 4 months and can include sleep disturbances, irritability and many more.⁶

What folate does in the brain

DNA and cell production

Folate plays a major role in the production of DNA and cell replication. When cells replicate, new DNA has to be synthesised. In order for this to happen, special reactions, known as methylation, must take place, resulting in the formation of nucleotides, which are a component of DNA. Folate enables these reactions to occur by providing a one-carbon group, which is a tiny building block made of just one carbon atom - they are also essential for making new DNA as they’re involved in DNA synthesis.¹ Because of this, folate is also considered to be a limiting factor which means too little folate can have an effect on essential genes and may cause alteration throughout an individual's life such as making them predisposed to certain neurological conditions.⁷

Brain development

As folate is vital for DNA synthesis, it’s important for all replicating cells and, therefore,  also necessary for brain development. During pregnancy, there is increased cell division, so pregnant women require significantly more folate, about 5-10 times the usual amount, for fetal growth and development.⁸ Folate has also been linked to the development of the neural tube during pregnancy. This is an early structure within the developing embryo that folds and closes between the 4th and 5th weeks of pregnancy to form the brain and the spinal cord. When there are issues with this process, it can result in neural tube defects (NTDs), the most fatal being anencephaly - this is when a baby is born missing parts of their brain and skull.⁹  Although the exact mechanism for how folate helps neural tube development beyond its role in DNA synthesis is still unknown, there have been various studies showing that low folate levels during early pregnancy increase the risk of NTDs.⁹ 

There's also a growing understanding that low folate during pregnancy can have long term effects on children, particularly on brain structure and function. Furthermore, early childhood studies have shown that children who were exposed to low folate in the uterus had smaller brain volumes from the third trimester into childhood, as well as reduced cerebral white matter in comparison to controls.¹ Studies conducted on children ages 12-18 months also showed that low levels of folate in the plasma were associated with poorer cognition.⁴

Folate is also needed for brain health throughout all stages of life. It’s required for the production of neurotransmitters which are chemical messengers within the body that allow signals to pass into the brain and thus, are vital for normal brain function.

How folate gets into the brain

Moving across the blood-brain barrier

The BBB regulates the exchange of essential nutrients from the blood to the brain in a highly selective manner in order to prevent any blood-borne toxins from entering, whilst providing the brain with the essentials needed for growth and maintenance. These nutrients are transported to the cerebral spinal fluid (CSF) at much higher concentrations than in the blood plasma, and by analysing this ratio, you can also determine the nutrient status of the brain.³

There are three ways that folate is able to enter the brain- these all require the help of specialised protein structures such as receptors and transporters, as most nutrients are unable to cross the BBB directly. These include:

• Folate receptor alpha (FRα) - This is the main way that folate enters the CSF from the blood plasma, and the receptor binds to folate at a high affinity, which means it binds very strongly, delivering high concentrations of it to the brain^10,11
• Reduced folate carrier (RFC) - This is a receptor with a lower affinity for folate and has a reduced uptake¹¹
• Protein-coupled folate transporter (PCFT) - This is a transporter protein that has a lower affinity to folate and is typically responsible for folate uptake in the intestines, but can still be found within the brain¹⁰

It’s important to note that the transport of folate via a receptor requires energy.¹⁰

What happens when folate can’t get in? 

CFD occurs when there is not enough folate within the CSF, despite normal levels elsewhere in the body. This deficiency can arise from various underlying issues, some of which are included below.

Mechanisms and causes of CFD:

• Reduced folate transport into the CFS due to disruption to the folate receptor alpha, for example)
• Depletion or impaired release of stored folate in the body
• Increased utilisation of folate within the nervous system
• Conditions affecting the metabolism of folate within the nervous system¹²
• Disruptions in FRα due to: 
• Autoantibodies - these are antibodies that can bind to the receptor and block it from binding or make it more difficult to bind, thus disrupting its function 
• Mitochondrial disease- transport through FRα requires energy from ATP, which is made within the mitochondria; therefore, a reduction of ATP
• Genetic mutations in genes encoding the transporters can disrupt the function of the transporters

Symptoms of CFD:

Symptoms can vary between individuals; some may have more pronounced symptoms than others. These can include:

• Irritability
• Seizures (especially in children with untreated CFD entering puberty)
• Vision problems
• Poor coordination
• Developmental delays
• Smaller head size 
• Trouble sleeping
• Tics
• Anxiety and depression

Diagnosis of CFD

• If CFD is suspected, there are various diagnostic tests that can be performed. The clinician will typically consider the patient’s age, medical history and symptoms, and may then recommend: Measuring active folate concentration in cerebral spinal fluid- This is usually achieved by a lumbar puncture procedure where a needle is inserted into the spinal canal
• Genetic testing for mutations in genes associated with CFD, such as the FOLR1 gene
• Testing for the presence of FRA autoantibodies, including both blocking and binding types
• Electroencephalography (EEG) - this detects any out-of-the-ordinary electrical activity in the brain, such as irregular waves (hypsarrhythmia)

Summary

Folate is an essential nutrient for brain development and function, playing key roles in DNA synthesis, cell replication, neurotransmitter production, and neural tube formation, with its transport across the BBB reliant on key receptors and transporters. Disruption in any part of this transport process can lead to cerebral folate deficiency (CFD). CFD can result from genetic mutations, autoantibodies, mitochondrial dysfunction, or impaired folate metabolism, highlighting the importance of early detection and diagnosis. Understanding the mechanisms behind folate transport and its disruption not only aids in diagnosing CFD but also emphasises the critical role of nutritional and molecular health in neurological development and maintenance throughout life.