Dietary choline phospholipids may be useful for slowing cognitive decline

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The initial 1000 days of life, spanning two years, are pivotal as they establish the groundwork for neurodevelopment.¹ Ensuring an ample intake of vital nutrients like folic acid, iron, iodine, and choline is essential during this period.

From among these, the ingredient choline, which shares close ties with the B-vitamin group, aids in the biosynthesis of a metabolite that is crucial for fetal development, particularly in brain development. Metabolically, choline is integral in synthesizing acetylcholine, phospholipids, and betaine.

But most importantly, choline is actively involved² in various neurochemical processes. It serves as a precursor and metabolite of acetylcholine (ACh), contributes to single-carbon metabolism, and is a crucial component of different membrane phospholipids (PLs). These choline phospholipidsare vital structural elements of cell membranes, playing essential roles in intraneuronal signal transduction.

Relevance of Choline Phospholipids to Brain Functional Pathways

In 1998, the Institute of Medicine officially acknowledged choline as an essential nutrient for the body. Its role within the system is multifaceted. It is indispensable for synthesizing the neurotransmitter acetylcholine (ACh), as well as for cell-membrane signaling phospholipids (PLs), lipid transport (lipoproteins) and methyl-group metabolism (plasma homocysteine reduction).²

Overall, the presence and balance of choline-containing phospholipids are critical for the proper functioning of brain cells and play a key role in various aspects of brain health and cognition.

Choline's necessity extends to the biosynthesis of crucial membrane components such as phosphatidylcholine (PC), lysophosphatidylcholine, choline plasmalogen and sphingomyelin, which are vital for all cell membranes.²

Particularly significant is the involvement of choline phospholipids in fetal brain and memory development, and there are studies to support this. One study³ that involved women in their third trimester of pregnancy divided them into two groups: one receiving 480 mg. of choline phospholipids and the other almost double that amount – 930 mg. Researchers assessed the babies' information processing speed at 4, 7, 10, and 13 months.

The findings revealed that infants born to mothers receiving the higher dose of choline phospholipids exhibited faster processing speeds. Interestingly, even among mothers given the lower dose, the longer the supplementation period, the quicker their child's reactions.

The study concluded that even modest increases in maternal choline phospholipids intake during pregnancy could yield cognitive benefits for offspring. Remarkably, seven years later, children whose mothers had received extra choline during pregnancy still displayed memory advantages.

Newborns enter the world with blood choline levels three times higher than their mothers, underscoring the nutrient's crucial role in building neuronal connections. Babies form up to a million new connections per second, highlighting the importance of optimal choline phospholipid intake for brain function.

Moreover, several prominent organizations, including the American Medical Association, the Committee on Nutrition1, and the American Academy of Paediatrics, have acknowledged the critical importance of choline phospholipids during pregnancy and early childhood.

Let's dive deep into why choline phospholipids are essential for brain function.

Choline is integral to brain cell membrane formation1, interacting with omega-3 fat DHA and other phospholipids. Without choline phospholipid, the omega-3 fat DHA cannot function properly. So, choline phospholipids play a crucial role in modifying the methylation patterns of brain DNA and histones, thereby influencing gene expression and the production of proteins involved in memory and learning. They have recently gained recognition as a 'neuroprotectant' and 'neurocognitive essential nutrient,' crucial for the normal growth and functioning of the developing brain.

Consequently, ensuring adequate choline phospholipid intake is imperative for maintaining optimal health.

However, the current dietary intake is lower because many individuals have decreased their consumption of high-cholesterol and fatty foods like eggs, meat, and dairy products, which are abundant sources of choline phospholipids.

Dietary Requirements of Choline Phospholipids

The dietary guidance for choline phospholipids from the European Food Safety Authority (EFSA) recommends an adequate intake (AI) of 400 mg/day for adults.¹ The AI represents the recommended average daily intake derived from estimates of nutrient consumption in healthy groups of people.

However, studies conducted in Europe and the Americas indicate a trend of average daily choline phospholipid intakes falling below the AI1. For instance, a study using data from European surveys found average intakes ranging from 291 to 374 mg/day among females aged 18 to ≤ 65.¹

Similarly, in the United States, based on data from the National Health and Nutrition Examination Survey, choline phospholipids intake for women of reproductive age was only 250 mg/day for females aged 19 to 30 years and 278 mg/day for those aged 31–50.

Unfortunately, given its broad impact on human metabolism, deficiencies in choline phospholipids can trigger diseases like non-alcoholic fatty liver disease, atherosclerosis (via lipoprotein secretion) and even potential neurological disorders and cognitive impairment cases.²

Potential Role of Choline Alfosceratein Slowing Cognitive Impairment

According to the 2020 United Nations report, 727 million individuals aged 65 or older worldwide are projected to exceed 1.5 billion by 2050.⁴ With this rapid demographic aging, there is an anticipated surge in age-related diseases and disabilities, with cognitive impairment assuming a significant role among them.

Cognitive impairment entails a gradual decline in learning and memory abilities, often leading to increased dependency and social isolation. It is estimated that 10% of individuals diagnosed with mild cognitive impairment progress to more serious issues each year⁴. As of 2019, there were 57.⁴ million people globally living with dementia, a number projected to reach 152.8 million by 2050.⁴

In this background, urgent action is required to implement strategies aimed at diagnosing initial cognitive impairment and halting or delaying its progression. Pharmacological interventions may play a crucial role in lessening the impact of cognitive impairment, particularly in delaying the progress of mild cognitive impairment.

Choline alphoscerate (alpha glyceryl phosphorylcholine, α-GPC) is a choline-containing phospholipid known for its cognition-enhancing properties.⁵ It is known to lead an increase in choline levels in the brain.

αGPC is a precursor to acetylcholine, increasing the brain's acetylcholine levels. Furthermore, αGPC influences cholinergic function and plays a role in monoaminergic transmission, affecting systems like dopaminergic and serotonergic pathways. These monoaminergic systems are associated with various emotional and motivational aspects, including reward processing, anxiety, depression and motivation.

From a pharmacological standpoint, α-GPC is recognized as a parasympathetic agent, utilized as a registered drug and nutraceutical in various countries. Preclinical research indicates that α-GPC enhances acetylcholine release and levels while facilitating learning and memory processes.⁵

Studies have demonstrated that α-GPC can also elevate acetylcholine levels.⁵ Acetylcholine is a neurotransmitter vital for inter-neuronal communication and communication between neurons, their skeletal muscles, and autonomic targets. It also plays a crucial role in the brain's capacity to store and retrieve information.

Clinical investigations have revealed that α-GPC improves cognition, behavior, and functional outcome.⁵

How α-GPC Increases Motivation in Healthy Volunteers

As discussed above, αGPC plays a crucial role in cholinergic function influences systems that are linked to emotions and feelings such as motivation, reward processing, anxiety, and depression.⁵

While the specific effects of αGPC on human emotions and feelings require further exploration, studies have aimed to investigate changes in the subjective feelings of healthy volunteers using the KOKORO scale before and after αGPC administration.⁵ The KOKORO scale is a user-friendly system that allows individuals to input mood information quickly using a touch panel or similar device.

In the study, 39 participants engaged in a single-blind, placebo-controlled design. They completed the KOKORO scale tests three times daily for two weeks before treatment and then for another two weeks during treatment self-administration.⁵

The results indicated a tendency for αGPC treatment to enhance motivation during the intervention. Mainly, motivation levels at night were significantly higher in the αGPC group compared to the placebo group (p < 0.05). These findings suggest that αGPC may effectively increase motivation in healthy individuals.

Need for More Research on the Role of Choline Phospholipids

Based on observations of reduced cholinergic neurotransmission in brain disorders marked by cognitive decline, cholinergic precursor loading therapy with choline-containing phospholipids (CCPLs) was initially explored as a potential approach to alleviating cognitive symptoms in Alzheimer's.⁶

Sadly, this therapeutic avenue was abandoned due to unfavourable clinical outcomes. The controlled clinical trials failed to demonstrate significant effects associated with choline or phosphatidylcholine (lecithin), another choline-containing phospholipid2. The reasons underlying the ineffectiveness of this precursor strategy remain unclear.

However, it is essential to note that adverse outcomes associated with certain compounds cannot be generalised to all compounds containing choline, known as choline-containing phospholipids (CCPLs). CCPLs have garnered significant interest in neuroscience and neurochemistry research, shedding light on various nerve cell membrane organization and function mechanisms.

CDP-choline and, to a greater extent, GPC have exhibited promising effects in preclinical and clinical studies, warranting further investigation. Given the limited availability of novel therapeutic strategies, well-established and safe compounds like effective CCPLs may still have a role in pharmacotherapy. Therefore, specific compounds of this class call for more research through new, appropriately designed clinical studies.

Parting Thoughts

Understanding the critical role of choline phospholipids in cognitive function and brain health offers insights into potential therapeutic avenues for various neurological conditions. From the crucial early developmental stages to the challenges of cognitive decline in later life, the significance of choline phospholipids remains profound.

While promising strides have been made in exploring the therapeutic potential of compounds like choline alphoscerate (GPC) in addressing cognitive impairment, further research is imperative to unlock their full therapeutic potential. As we delve deeper into the intricate workings of choline phospholipids, we pave the way for novel interventions that may alleviate the burden of cognitive decline and enhance brain health across the lifespan.

References

1. Derbyshire, E.; Obeid, R. Choline, Neurological Development and Brain Function: A Systematic Review Focusing on the First 1000 Days. Nutrients. 2020, 12 (6), 1731. DOI: 10.3390/nu12061731
2. Tayebati, S.K.; Amenta, F. Choline-containing phospholipids: relevance to brain functional pathways. Clinical Chemistry and Laboratory Medicine. 2013, 51 (3), 513-521. DOI: 10.1515/cclm-2012-0559 
3. West, A.A.; Yan, J.; Jiang, X.; Perry, C.A.; Innis, S.M.; Caudill, M.A. Choline intake influences phosphatidylcholine DHA enrichment in nonpregnant women but not in pregnant women in the third trimester. The American Journal of Clinical Nutrition. 2013, 97 (4), 718-727. DOI: 10.3945/ajcn.112.050211
4. Sagaro, G.G.; Traini, E.; Amenta, F. Activity of Choline Alphoscerate on Adult-Onset Cognitive Dysfunctions: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2023, 92 (1), 59-70. DOI: 10.3233/JAD-221189 
5. Tamura, Y.; Takata, K.; Matrubara, K.; Kataoka, Y. Alpha-Glycerylphosphorylcholine Increases Motivation in Healthy Volunteers: A Single-Blind, Randomized, Placebo-Controlled Human Study. Nutrients. 2021, 13 (6), 2091. DOI: 10.3390/nu13062091 
6. Tayebati, S.K.; Amenta, F. Choline-containing phospholipids: relevance to brain functional pathways. Clin Chem Lab Med. 2013, 51 (3), 513-521. DOI: 10.1515/cclm-2012-0559