Parkinson's disease and vitamins: a focus on vitamin B12

Abstract

Parkinson's disease (PD) has been linked to a vast array of vitamins among which vitamin B12 (Vit B12) is the most relevant and often investigated specially in the context of intrajejunal levodopa infusion therapy. Vit B12 deficiency, itself, has been reported to cause acute parkinsonism. Nevertheless, concrete mechanisms through which B12 deficiency interacts with PD in terms of pathophysiology, clinical manifestation and progression remains unclear. Recent studies have suggested that Vit B12 deficiency along with the induced hyperhomocysteinemia are correlated with specific PD phenotypes characterized with early postural instability and falls and more rapid motor progression, cognitive impairment, visual hallucinations and autonomic dysfunction. Specific clinical features such as polyneuropathy have also been linked to Vit B12 deficiency specifically in context of intrajejunal levodopa therapy. In this review, we explore the link between Vit B12 and PD in terms of physiopathology regarding dysfunctional neural pathways, neuropathological processes as well as reviewing the major clinical traits of Vit B12 deficiency in PD and Levodopa-mediated neuropathy. Finally, we provide an overview of the therapeutic effect of Vit B12 supplementation in PD and posit a practical guideline for Vit B12 testing and supplementation.

Keywords: Homocysteine; Motor; Non-motor; Parkinson’s disease; Vitamin B12; Vitamins.

Fig. 1

Illustration of the major water-soluble (in red) and fat-soluble vitamins (in blue) linked to neurodegenerative parkinsonian syndromes based on literature review. The green upper section includes the neurodegenerative parkinsonians syndromes cited below specific related vitamins. The orange section indicates the mechanisms of action of each of these vitamins in the CNS in relation with the pathophysiology of parkinsonian syndromes. The blue section points out the vitamin deficiencies associated to higher risk of developing PD and/or MSA (‘↑’:indicates higher risk of PD or MSA in case of the specified vitamin deficiency, ‘- ‘: indicates that the lack of evidence in literature findings. The grey section showcases the association of vitamin deficiency and greater progression in MSA/PD (‘↑’: indicates more rapid disease progression in case of the specified vitamin deficiency, ‘ = ’: indicated similar progression rate regarding the presence or not of vitamin deficiency, ‘- ‘: indicates that the relationship between the vitamin deficiency and PD/MSA has not been investigated). CNS central nervous system, PD Parkinson’s disease, MSA multiple system atrophy, SN Synuclein, Vit vitamin, *Neurodegenerative parkinsonian syndromes

Fig. 2

Pictorial illustration of the homocysteine methylation reaction into methionine (in purple) and its link with the cholinergic system. Illustrated in blue is the preferential pathway which is vitamin B-dependent (B12, B6, B9, B9) where the methylation process of homocysteine requires the synergic action of Vit B12 and MS. In Pink, if the secondary methylation pathway that is favored in case of Vit B12 deficiency pinpointing choline transformation to Betaine, the key ‘methyl’ donor for homocysteine. A joint pathway starts with the transformation of methionine into SAM. SAM will serve for the transformation of nicotinamide into N-methy-nicotinamide which inhibits competitively the efflux of choline out of the CNS. In yellow is the pathway of Levodopa transformation into dopamine and into 3-O-Methyl-Dopa. B6 vitamin B6, COMT Catheco-O-Methyl-transferase MAT methionine adenosyl-transferase, MS Methionine systhetase, PEMT Phosphatidyl-ethanolamine N-methyl-transferase, SAH S-adenosyl-homocysteine, SAM S-adenosyl- methionine, THF Tetrahydro-folate

Fig. 3

Summary of the different mechanisms of how Vit B12 could potentially interact with the physiopathology of PD. The yellow section focuses on evidence regarding the impact of Vit b12 deficiency on both cholinergic and dopaminergic pathways. The pink section summarizes how Vit B12 deficiency aggravates αSN pathology. Illustrated in the green section Vit B12 deficiency interaction with PD genetic background. In blue, the mechanisms of HHcy induced neurotoxicity in case of Vit B12 deficiency. The dotted pink arrow implies the presence of interaction between the two specified elements. NLRP-3 Nod-like receptor pyrin 3, NF-B nuclear factor kappa B, LRRK2 Leucine-Rich Repeat Kinase 2, αSN alpha-synuclein

Fig. 4

Potential causes of vitamin B12 deficiency in PD patients undergoing LCIG therapy. MMA: methylmalonic acid, LCIG levodopa–carbidopa intestinal gel; PEG percutaneous endoscopic gastrostomy, SIBO small intestinal bacterial overgrowth

Fig. 5

Flowchart of the proposed guidelines for the management of LCIG–treated patients. Step 1 (pre-assessment) is followed by the evaluation of Vit B12 serum levels as a main criterion to determine the following approach (Step 2). In step 3, based on Vit B12 status, supplementary clinical, laboratory and neurophysiological tests are indicated. Step 4 dictates how to approach HHcy or elevated MMA levels and neuropathy according to its severity. Step 5 is the supplementation protocole. Finally, step 6 pinpoints the monitoring approach. PD Parkinson disease, HHcy Hyperhomocisteinemia, ENG Electroneurography, EMG Electromyography, BMI Body-mass index, pg/ml picograms per milliliter, MMA Methylmalonic acid, PN peripheral neuropathy, LCIG levodopa–carbidopa intestinal gel, MTHFR Methylenetetrahydrofolatereductase, COMT-I Catechol-O-methyltransferase inhibitor, IM intramuscular, μg micrograms. *High risk patients = (advanced PD, diabetic patients, pre-existing PN)