Absorption de la vitamine B12 et maladie d'Alzheimer?

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Measuring vitamin B-12 bioavailability with [13C]-cyanocobalamin in humans
Sarita Devi, The American Journal of Clinical Nutrition, Volume 112, Issue 6, December 2020, Pages 1504–1515,

Background
Vitamin B-12 deficiency is widespread in many parts of the world, affecting all age groups and increasing with age. It is primarily due to a low intake of animal source foods or malabsorption. The measurement of bioavailability of vitamin B-12 is etiologically important in deficiency but is limited due to the use of radioactive isotopes like [57Co]- or [14C]-cyanocobalamin.

Objectives
The aim of this study was to measure the bioavailability of [13C]-cyanocobalamin in humans and to assess the effect of parenteral replenishment of vitamin B-12 on the bioavailability.

Methods
We synthesized a stable isotope-labeled vitamin B-12, [13C]-cyanocobalamin, using Salmonella enterica by providing [13C2]-ethanolamine as a sole carbon source. After purification and mass spectrometry–based characterization, its oral bioavailability was measured in the fasted state with high and low oral doses, before and after parenteral replenishment of vitamin B-12 stores, from the kinetics of its plasma appearance in a 2-compartment model.

Results
[13C]-cyanocobalamin was completely decyanated to [13C]-methylcobalamin describing metabolic utilization, and its plasma appearance showed early and late absorption phases. At a low dose of 2.3 µg, the mean bioavailability was 46.2 ± 12.8 (%, mean ± SD, n = 11). At a higher dose of 18.3 µg, the mean bioavailability was 7.6 ± 1.7 (%, mean ± SD, n = 4). Parenteral replenishment of the vitamin B-12 store in deficient individuals prior to the measurement resulted in a 1.9-fold increase in bioavailability.

Conclusions
Vitamin B-12 bioavailability is dose dependent and at a low dose that approximates the normal daily requirement (46%). The stable isotope method described here could be used to define the etiology of deficiency and to inform the dietary requirement in different physiologic states as well as the dose required for supplementation and food fortification

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On se focalise trop sur le taux d'absorption (théorique) des vitamines - minéraux. Sur une même personne, il varie grandement en fonction du dosage... et ce n'est qu'un des 10 paramètres qui modulent la biodisponibilité...

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High folic acid or folate combined with low vitamin B-12 status: potential but inconsistent association with cognitive function in a nationally representative cross-sectional sample of US older adults participating in the NHANES
Regan L Bailey, The American Journal of Clinical Nutrition, Volume 112, Issue 6, December 2020, Pages 1547–1557,

Background
Potential safety concerns relative to impaired cognitive function may exist when high folic acid exposures are combined with low vitamin B-12 status.

Objectives
We aimed to examine the relation of the coexistence of high folate and low vitamin B-12 status with cognitive function, utilizing various definitions of “high” folate status.

Methods
Cross-sectional data from older adults (≥60 y; n = 2420) from the 2011–2014 NHANES were analyzed. High folate status was defined as unmetabolized serum folic acid (UMFA) > 1 nmol/L or serum total folate > 74.1 nmol/L, and low vitamin B-12 status as methylmalonic acid > 271 nmol/L or serum vitamin B-12 < 150 pmol/L. Logistic regression models estimated ORs of scoring low on 1 of 4 cognitive tests: the Digit Symbol Substitution Test (DSST), the Consortium to Establish a Registry for Alzheimer's Disease Delayed Recall (CERAD-DR) and Word Learning tests, and the Animal Fluency test (AF).

Results
A significant interaction was observed relative to scoring low on the DSST (<34; UMFA; P-interaction = 0.0071) and AF (serum folate; P-interaction = 0.0078) for low vitamin B-12 and high folate status. Among those with low vitamin B-12, high UMFA or high serum total folate was associated with higher risk of scoring low on the DSST (OR: 2.16; 95% CI: 1.05, 4.47) and the AF (OR: 1.93; 95% CI: 1.08, 3.45). Among those with “normal” vitamin B-12, higher UMFA or serum total folate was protective on the CERAD-DR. In noninteraction models, when high folate and normal vitamin B-12 status was the reference group, low vitamin B-12 combined with high UMFA was associated with greater risk based on the DSST (<34, OR: 2.87; 95% CI: 1.85, 4.45; <40, OR: 2.22; 95% CI: 1.31, 3.75) and AF (OR: 1.97; 95% CI: 1.30, 2.97); but low vitamin B-12 and lower UMFA (OR: 1.69; 95% CI: 1.16, 2.47) was also significantly associated for DSST < 40 risk.

Conclusions
Low vitamin B-12 was associated with cognitive impairment both independently and in an interactive manner with high folate for certain cognitive performance tests among older adults.

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Traduction de l'étude

Acide folique ou folate élevé combiné à un faible statut en vitamine B-12: association potentielle mais incohérente avec la fonction cognitive dans un échantillon représentatif à l'échelle nationale d'adultes âgés américains participant au NHANES
Regan L. Bailey, The American Journal of Clinical Nutrition, Volume 112, Numéro 6, décembre 2020, Pages 1547-1557,

Contexte
Des problèmes de sécurité potentiels liés à une fonction cognitive altérée peuvent exister lorsque des expositions élevées à l'acide folique sont associées à un faible statut en vitamine B-12.

Objectifs
Nous avons cherché à examiner la relation entre la coexistence d'un statut élevé en folate et faible en vitamine B-12 avec la fonction cognitive, en utilisant diverses définitions du statut folate «élevé».

Méthodes
Des données transversales provenant d'adultes plus âgés (≥ 60 ans; n = 2420) de la NHANES 2011-2014 ont été analysées. Un statut élevé en folate était défini comme un acide folique sérique non métabolisé (UMFA)> 1 nmol / L ou un taux sérique d'acide folique total> 74,1 nmol / L, et un faible statut en vitamine B-12 en acide méthylmalonique> 271 nmol / L ou en vitamine B-12 sérique 150 pmol / L. Les modèles de régression logistique ont estimé les OR de scores faibles sur l'un des 4 tests cognitifs: le test de substitution de symboles numériques (DSST), le consortium pour établir un registre pour le rappel différé de la maladie d'Alzheimer (CERAD-DR) et les tests d'apprentissage de mots, et le test de fluidité animale (UN F).

Résultats
Une interaction significative a été observée par rapport à un score faible sur le DSST (<34; UMFA; P-interaction = 0,0071) et AF (folate sérique; P-interaction = 0,0078) pour un faible taux de vitamine B-12 et un taux élevé de folates. Parmi les personnes ayant une faible teneur en vitamine B-12, une teneur élevée en UMFA ou en folate total sérique élevé était associée à un risque plus élevé d'obtenir un score faible au DSST (OR: 2,16; IC à 95%: 1,05, 4,47) et à la FA (OR: 1,93; 95% CI: 1,08, 3,45). Parmi ceux avec de la vitamine B-12 «normale», une teneur plus élevée en UMFA ou en folate total sérique était protectrice sur le CERAD-DR. Dans les modèles de non-interaction, lorsque le taux de folate élevé et le statut normal en vitamine B-12 étaient le groupe de référence, un faible taux de vitamine B-12 combiné à un taux élevé d'UMFA était associé à un risque plus élevé selon le DSST (<34, OR: 2,87; IC à 95%: 1,85 , 4,45; <40, OR: 2,22; IC à 95%: 1,31, 3,75) et AF (OR: 1,97; IC à 95%: 1,30, 2,97); mais une faible teneur en vitamine B-12 et une teneur en UMFA inférieure (OR: 1,69; IC à 95%: 1,16, 2,47) étaient également significativement associées au risque de DSST <40.

Conclusions
Une faible teneur en vitamine B-12 était associée à une déficience cognitive à la fois indépendamment et de manière interactive avec une forte teneur en acide folique pour certains tests de performance cognitive chez les personnes âgées.

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Vitamin B12 impacts amyloid beta-induced proteotoxicity by regulating the methionine/S-adenosylmethionine cycle
Andy B. Lam cell rep. VOLUME 36, ISSUE 13, 109753, SEPTEMBER 28, 2021

• Dietary vitamin B12 reduces the proteotoxic effects of Aβ in C. elegans
• Vitamin B12 is protective even when given to deficient worms only during adulthood
• B12 has this impact by acting in C. elegans as a cofactor for methionine synthase

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis, including amyloid beta (Aβ) deposition, energy crisis, and oxidative stress. Here, we use Caenorhabditis elegans to define the impact of diet on Aβ proteotoxicity.

We discover that dietary vitamin B12 alleviates mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying Aβ-induced paralysis without affecting Aβ accumulation. Vitamin B12 has this protective effect by acting as a cofactor for methionine synthase, impacting the methionine/S-adenosylmethionine (SAMe) cycle. Vitamin B12 supplementation of B12-deficient adult Aβ animals is beneficial, demonstrating potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by proteotoxic stress.

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Traduction de l'étude

La vitamine B12 a un impact sur la protéotoxicité induite par la bêta-amyloïde en régulant le cycle méthionine/S-adénosylméthionine
Andy B. Lam représentant cellulaire. VOLUME 36, NUMÉRO 13, 109753, 28 SEPTEMBRE 2021

• La vitamine B12 alimentaire réduit les effets protéotoxiques de l'Aβ chez C. elegans
• La vitamine B12 est protectrice même lorsqu'elle est administrée à des vers déficients uniquement à l'âge adulte
• B12 a cet impact en agissant dans C. elegans comme cofacteur de la méthionine synthase

La maladie d'Alzheimer (MA) est une maladie neurodégénérative dévastatrice sans traitement efficace. L'alimentation, en tant que facteur de risque modifiable de la MA, pourrait potentiellement être ciblée pour ralentir l'apparition et la progression de la maladie. Cependant, la complexité de l'alimentation humaine et les effets indirects du microbiome rendent difficile l'identification des nutriments protecteurs. De multiples facteurs contribuent à la pathogenèse de la MA, notamment le dépôt de bêta-amyloïde (Aβ), la crise énergétique et le stress oxydatif. Ici, nous utilisons Caenorhabditis elegans pour définir l'impact de l'alimentation sur la protéotoxicité de l'Aβ.

Nous découvrons que la vitamine B12 alimentaire atténue la fragmentation mitochondriale, les défauts bioénergétiques et le stress oxydatif, retardant la paralysie induite par Aβ sans affecter l'accumulation d'Aβ. La vitamine B12 a cet effet protecteur en agissant comme cofacteur de la méthionine synthase, impactant le cycle méthionine/S-adénosylméthionine (SAMe). La supplémentation en vitamine B12 des animaux adultes Aβ déficients en B12 est bénéfique, démontrant le potentiel de la vitamine B12 en tant que thérapie pour cibler les caractéristiques pathogènes de la MA déclenchée par un stress protéotoxique.

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Vitamin B12 absorption and malabsorption
Vitamins and Hormones Volume 119, 2022, Pages 241-274 Jean-Louis Guéant

Vitamin B12 is assimilated and transported by complex mechanisms that involve three transport proteins, intrinsic factor (IF), haptocorrin (HC) and transcobalamin (TC) and their respective membrane receptors. Vitamin deficiency is mainly due to inadequate dietary intake in vegans, and B12 malabsorption is related to digestive diseases. This review explores the physiology of vitamin B12 absorption and the mechanisms and diseases that produce malabsorption.

In the stomach, B12 is released from food carrier proteins and binds to HC. The degradation of HC by pancreatic proteases and the pH change trigger the transfer of B12 to IF in the duodenum. Cubilin and amnionless are the two components of the receptor that mediates the uptake of B12 in the distal ileum. Part of liver B12 is excreted in bile, and undergoes an enterohepatic circulation.

The main causes of B12 malabsorption include inherited disorders (Intrinsic factor deficiency, Imerslund-Gräsbeck disease, Addison's pernicious anemia, obesity, bariatric surgery and gastrectomies. Other causes include pancreatic insufficiency, obstructive Jaundice, tropical sprue and celiac disease, bacterial overgrowth, parasitic infestations, Zollinger-Ellison syndrome, inflammatory bowel diseases, chronic radiation enteritis of the distal ileum and short bowel. The assessment of B12 deficit is recommended in the follow-up of subjects with bariatric surgery. The genetic causes of B12 malabsorption are probably underestimated in adult cases with B12 deficit. Despite its high prevalence in the general population and in the elderly, B12 malabsorption cannot be anymore assessed by the Schilling test, pointing out the urgent need for an equivalent reliable test.

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Telomere length and vitamin B12
Guruvaiah Praveen Vitamins and Hormones Volume 119, 2022, Pages 299-324

Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging.

Telomere length (TL) is thereby an ideal candidate for “biological aging.” Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL.

Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.

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Behavioral profile of vitamin B12 deficiency: A reflection of impaired brain development, neuronal stress and altered neuroplasticity
Grégory Pourié Vitamins and Hormones Volume 119, 2022, Pages 377-404

Our understanding of brain biology and function is one of the least characterized and therefore, there are no effective treatments for most of neurological disorders. The influence of vitamins, and particularly vitamin B12, in neurodegenerative disease is demonstrated but largely unresolved. Behaviors are often quantified to attest brain dysfunction alone or in parallel with neuro-imaging to identify regions involved. Nevertheless, attention should be paid to extending observations made in animal models to humans, since, first, behavioral tests have to be adjusted in each model to address the initial question and second, because brain analysis should not be conducted for a whole organ but rather to specific sub-structures to better define function.

Indeed, cognitive functions such as psychiatric disorders and learning and memory are often cited as the most impacted by a vitamin B12 deficiency. In addition, differential dysfunctions and mechanisms could be defined according sub-populations and ages. Vitamin B12 enters the cell bound to Transcobalamin, through the Transcobalamin Receptor and serves in two cell compartments, the lipid metabolism in the mitochondrion and the one-carbon metabolism involved in methylation reactions. Dysfunctions in these mechanisms can lead to two majors outcomes; axons demyelinisation and upregulation of cellular stress involving mislocalization of RNA binding proteins such as the ELAVL1/HuR or the dysregulation of pro- or anti-oxidant NUDT15, TXNRD1, VPO1 and ROC genes. Finally, it appears that apart from developmental problems that have to be identified and treated as early as possible, other therapeutic approaches for behavioral dysfunctions should investigate cellular methylation, oxidative and endoplasmic reticulum stress and mitochondrial function.

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Vitamin B12 deficiency
Ralph Green Vitamins and Hormones Volume 119, 2022, Pages 405-439

Of the water-soluble vitamins, vitamin B12 (B12) has the lowest daily requirement. It also has several unique properties including a complex pathway for its absorption and assimilation requiring intact gastric and terminal small intestinal function, an enterohepatic pathway, and several dedicated binding proteins and chaperons. The many causes of B12 deficiency include malabsorption and defects in cellular delivery and uptake, as well as limited dietary intake. B12 is required as a cofactor for only two reactions in humans, the cytosolic methionine synthase reaction and the mitochondrial methymalonyl CoA mutase reaction. Disruption of either of these reactions gives rise to B12 deficiency.

Although more common with advancing age, because of the higher prevalence of malabsorptive disorders in the elderly, B12 deficiency is widely distributed across all age groups particularly where food insecurity occurs. The consequences and severity of B12 deficiency are variable depending on the degree of deficiency and its duration. Major organ systems affected include the blood, bone marrow and nervous system. Megaloblastic anemia results from a defect in thymidine and therefore DNA synthesis in rapidly dividing cells. Nervous system involvement is varied, some of which results from defective myelin synthesis and repair. Cognitive impairment and psychosis may also occur. Diagnosis of B12 deficiency rests on clinical suspicion followed by laboratory testing, which consists of a panel of tests, that together provide clinically reliable predictive indices. B12 metabolism and deficiency is closely intertwined with folate, another B-vitamin. This chapter explores the various aspects of a unique and fascinating micronutrient.

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Neuropsychiatric manifestations in vitamin B12 deficiency
Vitamins and Hormones Volume 119, 2022, Pages 457-470 Prashant Sahu

Vitamin B12 deficiency can have distressing neuropsychiatric symptoms. It can have an etiological role in clinical presentations like depression, anxiety, psychosis, dementia, and delirium, requiring screening of at-risk populations. Few mechanisms that underlie the neuropsychiatric manifestations of B12 deficiency include alteration in one-carbon metabolism, genetic vulnerability, and alteration in folate metabolism. Maintaining a high serum B12 level in elderly can be protective against Alzheimer's disease (AD). In an established AD, its deficiency is associated with higher cognitive decline and risk for delirium. The other mental changes associated with B12 deficiency include apathy, agitation, impaired concentration, insomnia, persecutory delusions, auditory and visual hallucinations, and disorganized thought-process. Besides serum vitamin B12, plasma methylmalonic acid (MMA) and homocysteine helps in diagnosis. The chapter focuses on early recognition and effective treatment of these neuropsychiatric manifestations of vitamin B12 deficiency.

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Traduction de l'étude

Manifestations neuropsychiatriques de la carence en vitamine B12
Vitamines et Hormones Volume 119, 2022, Pages 457-470 Prashant Sahu

Une carence en vitamine B12 peut avoir des symptômes neuropsychiatriques pénibles. Il peut avoir un rôle étiologique dans des présentations cliniques telles que la dépression, l'anxiété, la psychose, la démence et le délire, nécessitant un dépistage des populations à risque. Peu de mécanismes qui sous-tendent les manifestations neuropsychiatriques de la carence en B12 comprennent l'altération du métabolisme à un carbone, la vulnérabilité génétique et l'altération du métabolisme des folates. Le maintien d'un taux sérique élevé de B12 chez les personnes âgées peut être protecteur contre la maladie d'Alzheimer (MA). Dans une DA établie, sa déficience est associée à un déclin cognitif plus élevé et à un risque de délire. Les autres changements mentaux associés à une carence en vitamine B12 comprennent l'apathie, l'agitation, les troubles de la concentration, l'insomnie, les délires de persécution, les hallucinations auditives et visuelles et le processus de pensée désorganisé. Outre la vitamine B12 sérique, l'acide méthylmalonique plasmatique (MMA) et l'homocystéine aident au diagnostic. Le chapitre se concentre sur la reconnaissance précoce et le traitement efficace de ces manifestations neuropsychiatriques de la carence en vitamine B12.

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Vitamins:a nutritional intervention to modulate the Alzheimer’s disease progression
Jahangir Alam Nutritional Neuroscience Volume 25, 2022 - Issue 5 Pages 945-962

Background: Alzheimer’s disease is known as one of the fastest growing lethal diseases worldwide where we have limited and undesired ways for regulating its pathological progress. Now-a-days, nutritional compounds have been using to treat several brain disorders and one of them; vitamins were strongly reported to combat cognition and memory deterioration in neurodegenerative diseases including Alzheimer’s disease.

Objective: Here, the author tried to find the precise physiological roles, status, and worth of vitamins in the brain and how exactly these nutrients modulate progression of Alzheimer’s disease.

Results & Discussion: After a comprehensive and systematic literature review, the author reports that vitamins have various targets in Alzheimer’s disease pathogenesis by which they act to avert the neuronal dysfunction in the disease. Several Alzheimer’s disease-associated neurological deficits have reported regulating by vitamin intake but the beneficial effects identified mostly in combinatorial and long-term studies.

Conclusion: In this way, the author suggests that it might be better to test vitamins with other components over single vitamin approach for a compatible and synergistic effect as well as using a combination of vitamin with other compounds can target multiple pathways. This strategy may help in deteriorating memory dysfunction and cognition impairment in Alzheimer’s disease pathophysiology.

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Traduction de l'étude

Vitamines : une intervention nutritionnelle pour moduler la progression de la maladie d’Alzheimer
Jahangir Alam Nutritional Neuroscience Volume 25, 2022 - Numéro 5 Pages 945-962

Contexte : La maladie d'Alzheimer est connue comme l'une des maladies mortelles à la croissance la plus rapide dans le monde, où nous disposons de moyens limités et indésirables pour réguler sa progression pathologique. De nos jours, les composés nutritionnels sont utilisés pour traiter plusieurs troubles cérébraux et l'un d'entre eux ; les vitamines ont été fortement signalées pour lutter contre la détérioration de la cognition et de la mémoire dans les maladies neurodégénératives, y compris la maladie d'Alzheimer.

Objectif : Ici, l'auteur a essayé de trouver les rôles physiologiques précis, le statut et la valeur des vitamines dans le cerveau et comment exactement ces nutriments modulent la progression de la maladie d'Alzheimer.

Résultats et discussion : Après une revue de littérature complète et systématique, l'auteur rapporte que les vitamines ont diverses cibles dans la pathogenèse de la maladie d'Alzheimer par lesquelles elles agissent pour éviter le dysfonctionnement neuronal dans la maladie. Plusieurs déficits neurologiques associés à la maladie d'Alzheimer ont rapporté une régulation par l'apport en vitamines, mais les effets bénéfiques ont été identifiés principalement dans des études combinatoires et à long terme.

Conclusion : De cette manière, l'auteur suggère qu'il serait peut-être préférable de tester les vitamines avec d'autres composants plutôt qu'une approche à une seule vitamine pour un effet compatible et synergique, ainsi que d'utiliser une combinaison de vitamines avec d'autres composés pouvant cibler plusieurs voies. Cette stratégie peut aider à détériorer le dysfonctionnement de la mémoire et les troubles cognitifs dans la physiopathologie de la maladie d'Alzheimer.