Thursday, 26 April 2018

Homocysteine on the brain - many paths to many problems

Homocysteine might be important in many neurological disorders, especially cognitive decline. I’ve been reading about potential mechanisms – there are a lot! Here’s an attempt to arrange all the interesting stuff as a mini-review.

Homocysteine?

Homocysteine is a sulfur-containing amino acid, derived from the metabolism of dietary methionine. Homocysteine exists in various forms 1 and is metabolised via two main pathways - remethylation and transsulfuration. Homocysteine remethylation to methionine maintains levels of SAM, the major methyl-donor, required in over 50 methylation reactions to DNA/RNA, proteins, phospholipids and other metabolites 2. Whereas homocysteine catabolism via the transsulfuration pathway yields many other important sulfur metabolites (e.g. cysteine/glutathione, H2S and taurine). Both of these pathways depend upon B vitamin-derived substrates/cofactors and are regulated by various physiological processes.

Elevated homocysteine (hyperhomocysteinemia) is a promiscuous marker of dysregulated metabolism associated with many diseases. The most severely elevated homocysteine occurs with rare genetic mutations (e.g. CBS 3 and MTHFR 4). Whereas moderately elevated homocysteine is associated with many conditions, in relation to genetic, nutrition and other factors. In particular, elevated homocysteine is associated with brain diseases, including neuropsychiatric conditions (e.g. depression), cognitive decline, stroke, vascular dementia and Alzheimer’s disease, as well as related pathogenic factors, including brain atrophy, white matter hyperintensities (WMH), cerebral perfusion and metabolite markers (e.g. NAA and creatine), suggesting importance to brain function 5–11!

In the brain

Each organ, and even cell, has different/unique functions and metabolic needs. So it’s important to consider things in a compartment-specific manner.

The brain is composed largely of lipids, with intricate signaling processes and massive fuel/oxygen requirements (20% of resting body metabolism), all of which heavily depend upon sulfur/methylation processes. Methylation is important for the regulation of genes and proteins, as well as the metabolism of many brain molecules (e.g. phospholipids, myelin, creatine and neurotransmitters). As in other tissues, the brain has a primary MS-dependant methylation pathway 12–14. However, under certain conditions, cortical neurons may also express a BHMT pathway, previously thought only to exist in the liver and kidneys 15. The brain also expresses transsulfuration pathways in neurons and glia, which are regulated by activity and produce a variety of metabolites with antioxidant and signaling activities 16–18.

The brain exists within a distinct compartment of the body, separated by barriers between blood, brain and cerebrospinal fluid (CSF), and therefore represents a specific metabolic environment. There are major differences between blood and CSF levels of sulfur/methylation metabolites, although they are correlated 19,20. Human CSF has lower levels of methionine, homocysteine (>100x!), SAH, cystathionine and holoTC, while higher levels of SAM, MMA and folate (methyl-THF) 19,20. Therefore, there is a higher methylation ratio (SAM/SAH) in CSF than blood. In animals, SAH and SAM/SAH ratios are correlated between CSF and brain 21. In humans, CSF and brain methylation markers are altered in aging and various neurological diseases, suggesting impaired methylation potential 4,6,12,20,22.

Many pathways…

What happens when things go wrong? Experimental research has shown that dysregulation of homocysteine metabolism can induce many changes (e.g. signaling systems, metabolism, inflammation and neuroplasticity) which may underlie impaired cognition and mood 5–9. Homocysteine itself has many dose-dependent effects on specific brain cells (i.e. neurons, glia and vascular cells) 8, microglial activation (inflammation) 23,24 and synaptic plasticity 25. Even mildly elevated homocysteine can promote brain inflammation, acetylcholine catabolism and cell damage 26,27. Some of the major mechanisms involved are discussed briefly below.

NMDA receptors

Effects of homocysteine are mediated both directly and via derivatives (e.g. homocysteic acid and homocysteine thiolactone). Most typically, homocysteine activates NMDA receptors, preferentially of GluN2A subunit composition (EC50 9.7uM), and perhaps in concert with mGluR5 28. Moreover, an oxidised form of homocysteine, homocysteic acid, seems even more neuroactive 29. Under normal conditions, homocysteine levels may be quite low in the brain 30,31 and extracellular space 32. However, homocysteic acid is concentrated in glial cells and may serve as a physiological gliotransmitter which activates NMDA receptors 30. Chronic mild stress can also induce homocysteine release, resulting in NMDA receptor activation and depressive behaviours 31. Homocysteine can also impair cerebral blood flow and blood-brain barrier function via activation of endothelial NMDA receptors 33,34.

Methylation

Impaired homocysteine metabolism is typically accompanied by lower SAM and/or higher SAH (due to inhibition or reversal of SAHH), which inhibits most methylation reactions 2,35. One of the major consumers of methyl groups is phosphatidylcholine (PC) synthesis 36. A folate deficient diet caused depletion of brain PC, which predicted cognitive impairment better than blood homocysteine or brain SAM/SAH 37. Folate and SAM may also maintain brain choline and acetylcholine 38. In the brain of people with dementia, elevated SAH was associated with inhibition of enzymes which methylate neurotransmitters (e.g. COMT and PNMT) and cognitive impairment 39. Both folate and methylation pathways are also required for DNA synthesis and cell replication. Dietary folate deficiency suppresses cell proliferation and neurogenesis, while uracil misincorporation may contribute to behavioural effects and neurodegeneration 40. Methylation of genes and proteins regulates many background housekeeping processes, as well as learning and memory 41. In animal models of dementia, impaired homocysteine metabolism leads to hypomethylation of genes and proteins in pathways controlling protein processing 6,42,43 and inflammation 44–46, resulting in neuropathology and cognitive decline (see below). In the brain of people with multiple sclerosis, betaine and SAM deficiency were linked to impaired epigenetic regulation of mitochondrial respiration 15.

Transsulfuration

Homocysteine catabolism via the transsulfuration pathway yields several important metabolites (e.g. cysteine/glutathione, H2S, lanthionine and taurine) with neuroprotective, antioxidant and signaling activity 16–18,47,48. Some of these metabolites may be depleted in neurological disorders. For instance, in animal models brain H2S can be suppressed by homocysteine 49, inflammation 50 and chronic stress 51. The transsulfuration enzymes are also B6-dependant and flux through this pathways is regulated by SAM 52, which stimulates neuronal CBS and H2S production 53,54. H2S supports many important neurological processes 18 and is protective via multiple mechanisms in animal models of depression 51, neuroinflammation 50 and dementia 55. In particular, H2S often has opposite effects to homocysteine and offsets its damaging effects 56. For instance, brain administration of homocysteine induced vascular inflammation and impaired cerebral blood flow, blood-brain barrier and synaptic plasticity, which was prevented by blocking NMDA receptors or boosting H2S 33. In the brain, the transsulfuration pathway is also a source of cysteine for synthesis of glutathione 17, a major cellular antioxidant often depleted in neurological disorders. Note, H2S promotes glutathione synthesis 18, while SAM regulates glutathione utilisation via the GST enzymes 57,58.

Alzheimer’s, amyloid and tau

Since the early 90s 59, many studies have associated lower B vitamin and higher homocysteine levels with Alzheimer’s disease 6. Remarkably, since the early 2000s 7,60,61, experimental research has shown that B vitamin deficiency and homocysteine derivatives (i.e. SAH 62, homocysteic acid 63 and homocysteine thiolactone 64) can promote the major hallmarks of Alzheimer’s 6,42 – i.e. amyloid-β accumulation and tau hyperphosphorylation, which underlie the formation of senile plaques and neurofibrillary tangles respectively (for animation see Nature video).

Alzheimer’s is the commonest form of dementia and develops slowly over many years/decades in relation to genetic and environmental risk factors. It’s now possible to measure biomarkers of brain amyloid and tau in people via CSF and brain PET, which may become increasingly abnormal as people progress from subjective cognitive impairment (SCI) to mild cognitive impairment (MCI) to dementia 65,66. Moreover, recently it was reported that even in cognitively normal older adults, brain amyloid and tau accumulation was related to depression/anxiety symptoms 67,68. In other words, amyloid and tau are on the scene long before dementia!

Some studies find correlations with sulfur metabolism in blood, CSF or brain. For instance, in CSF, there were correlations between markers of homocysteine metabolism and amyloid-β in healthy adults (age = 43.7) 69, which may be lost during cognitive decline as amyloid-β42 is retained in the brain 69,70; while other studies find correlations with tau/p-tau 71. In older adults with SCI (the earliest stage of cognitive decline), brain amyloid burden (PET) was related to plasma homocysteine, but only when combined with a low omega-3 index 72. Also in a small study on healthy older adults (aged 55-75), brain glutathione (MRS) was inversely related to brain amyloid (PET), but not cognition 73.

Amyloid-β peptides are derived from the amyloid precursor protein (APP). APP is cut by α, β and γ-secretases into specific peptide fragments with various functions, while accumulation of amyloid-β can be neurotoxic. In cell and animal models, depletion of B vitamins lowers the SAM/SAH ratio and induces expression of BACE and PS1 (and thereby β and γ-secretase activity respectively), amyloid-β accumulation and cognitive impairment 60,74. Note, early cognitive impairment paralleled amyloid-β in neurons, before plaque formation 74. Moreover, folate not only suppressed BACE and PS1, but induced the expression of ADAM9 and 10 (i.e. α-secretase activity), thereby diverting APP away from the amyloid-β pathway 75. Some recent research suggests H2S may also regulate APP processing 76. Interestingly, chronic stress can also alter APP processing and induce intracellular amyloid accumulation and cognitive decline, which is dependent upon impaired homocysteine metabolism 77.

Homocysteine also regulates tau phosphorylation. Tau is a microtubule-associated protein (MAP) which regulates microtubule stability, but becomes pathogenic when hyperphosphorylated. Tau phosphorylation is regulated by various kinases (add phosphate) and phosphatases (remove phosphate). B vitamin deficiency and homocysteine promote tau hyperphosphorylation in relation to both hypomethylation of PP2A 43, which inhibits phosphatase activity, and activation of NMDA receptors 78 and GSK3β 79, which promote kinase activity. A particularly incriminating piece of evidence is the co-localisation of demethylated PP2A with hyperphosphorylated tau in the hippocampus of animal models and Alzheimer’s 80.

Most recently, homocysteine metabolism was linked to Alzheimer’s-type pathology via the 5-lipoxygenase (5-LO) inflammatory pathway 44–46. Specifically, dietary B vitamin deficiency increased homocysteine and lowered SAM/SAH, resulting in hypomethylation of the ALOX5 gene and increased 5-LO activity. This pathway was required for amyloid accumulation, tau phosphorylation, neuroinflammation, synaptic pathology and cognitive dysfunction, underscoring its importance 45,46. It was also required for increased γ-secretase and CDK5, which regulate amyloid and tau respectively 46, suggesting it lies upstream of changes reviewed above. The 5-LO enzyme metabolises essential fatty acids (e.g. AA) to immune signaling molecules (e.g. LTB4), and its expression increases during ageing and in Alzheimer’s 81. Note, 5-LO also acts on EPA, so may be influenced by omega-3 status 82.

VITACOG – dementia prevented?

Despite all the plausibility from association and experimental research, to definitively prove homocysteine metabolism is causal in human disease, we need trials to modulate it. This is where things often get messy – humans are varied. Systematic reviews and meta-analyses which combine the results of homocysteine-lowering trials report an overall failure to improve cognitive outcomes 83,84. However, most trials had major limitations (e.g. inappropriate cohorts, poor quality inventions, limited cognitive tests, no objective brain tests and no subgrouping) 8,85. Crucially, if you only consider trials which included those likely to benefit (i.e. people with cognitive decline and nutrient deficiency!), then there may be benefit (for reviews see 8,85,86).

The most convincing and promising trial I am aware of was the VITACOG trial. This was a placebo-controlled, randomised trial of B vitamins (20mg B6, 0.8mg B9 and 0.5mg B12), in 271 elderly people (age 70) with MCI, lasting 2 years and reporting on various outcomes – brain atrophy (primary), blood biomarkers and cognition (secondary) 87–91. In the placebo group, blood homocysteine positively correlated brain atrophy rate, while in the active group there was a slowing of whole brain atrophy 88. Further analysis showed the rate of atrophy was up to 7-fold lower in specific regions associated with Alzheimer’s disease (Fig 1) 87. Slowing of brain atrophy and cognitive decline were confined to those with elevated homocysteine at baseline (>11uM) 87,89, while in people with levels >13uM clinical outcomes actually improved, suggesting reversal of MCI 89. Benefits were also dependant on higher blood omega-3 status (EPA and DHA) at baseline 90,91. Whereas treatment was less effective in those taking aspirin 88 (as with CVD trials 85). Consequently, this research suggests why many previous trials may have failed, and has identified subgroups which may respond to B vitamins.

To put this research in context, 8-25% of people over 60 have MCI, of which 5-17% convert to Alzheimer’s each year 66. Alzheimer’s is the commonest form of dementia and rates are increasing, with massive socioeconomic impact (Alzheimer's Society). In the UK, 225,000 people develop dementia every year - roughly 1 person every 3 mins; and by 2050, there may be 2 million people with dementia. Currently, there are only a handful of symptomatic drugs, none of which slow disease progression 92. So once you recover from the shock of diagnosis, you must prepare for your decline and get things in order (NHS).

On the other hand, experts believe dementia is not normal ageing and can be prevented (statement supported by over 100 scientists) 93. The seeds of dementia develop slowly over many years/decades, as people progress from SCI to MCI to dementia 65,66. This suggests enormous potential for prevention with modifiable risk factors (e.g. TED talk). Elevated homocysteine is associated with age, neurological diseases and pathogenic pathways, as discussed above. Researchers feel further high-quality trials and government funding are urgently needed to test whether (non-patentable) nutrient therapies can help prevent cognitive decline and progression to dementia 86,94.

In particular, perhaps metabolic interventions could be better? For instance, one basic aspect of most B vitamin trials (incl. VITACOG) is they used the synthetic form of folate – folic acid, rather the naturally occurring reduced form – 5-methyl-THF. They are not the same thing 95, and may not have the same efficacy 96,97. Diet/metabolic interventions could also be far more comprehensive 98.

How about reversal of Alzheimer’s disease - is that possible?! Interestingly, a recent small study, on 10 people with MCI and early Alzheimer’s disease, reported that a comprehensive individualised approach (incl. diet, lifestyle, nutrients and drugs) could reverse cognitive decline and neuroimaging abnormalities 99,100 (for more see YouTube and Cort’s post). Furthermore, another line of research suggests targeting homocysteic acid may be of major therapeutic benefit 61,63,101,102. In particular, in a recent open label trial on 91 Alzheimer’s disease patients, 2 months treatment with a multi-component supplement, called hydrogen brain food (HBF), lowered homocysteic acid and improved cognition in all patients, even those with final-stage disease 101!

Phospholipid methylation?

The interactions between omega-3 status and treatment response in VITACOG could involve several mechanisms, one of which is phospholipid methylation 90,91. So here’s a bit more on this.

Phospholipids are the major component of cell membranes. They are composed of fatty acid tails joined to a phosphate head group with various modifications. Methylation is involved in the synthesis of phosphatidylcholine (PC), the most abundant phospholipid in cells and plasma. Most PC is synthesised by the CDP-choline (Kennedy) pathway, the rest via methylation. Crucially, these pathways are not interchangeable and produce PC of different fat profiles 103–105. PC from the CDP-choline pathway mainly contains medium-chain saturated fats, whereas PC from the methylation pathway is richer in long-chain polyunsaturated fats (incl. DPA and DHA) (Fig 3), which may also have a faster cellular turnover 105. Phospholipid methylation is mediated by the enzyme PEMT, which transfers 3 methyl groups to phosphatidylethanolamine (PE) to generate PC. This represents the only pathway for de novo choline synthesis and one of the major methyl consumers in the body 36. PEMT activity is highest in the liver and related to plasma PC-DHA content in humans 106. Blood PC-DHA can be delivered to the brain, although the brain also has some PEMT activity 107, which may be particularly important at synapses 103,104. Note, a folate deficient diet markedly suppressed brain PC and elevated PE, supporting the importance of phospholipid methylation 37.

PC is important for cell membrane structure and function, and also represents a reservoir of choline for acetylcholine synthesis, which may be liberated if demand exceeds supply 37. There are many associations between PC/DHA, cognition and neurological disorders in humans and experimental models (for reviews see 107,108). This relationship may involve methylation 107. For instance, in healthy humans, there are correlations between the plasma methylation potential (SAM/SAH) and PC-DHA content 106. Similarly, in people with dementia, plasma homocysteine correlated SAH, which inversely correlated the PC/PE ratio and PC-DHA content in RBCs 109. Furthermore, another study found low brain PEMT activity which may also impair local PC synthesis 110. Importantly, in an animal model of folate deficiency, depletion of brain PC predicted cognitive impairment better than blood homocysteine or brain SAM/SAH 37.

Finally it seems worth noting that NMDA receptor over-activation can also inhibit PC and PE synthesis via the Kennedy pathway 111. So perhaps elevated homocysteine could promote this mechanism too?

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