1.9 B vitamins & homocysteine
1.9.3 Homocysteine and neurocognitive disease
homocysteine may have a contributing role. In the early 1990s two articles were published presenting the hypothesis that homocysteine metabolism might play a role in the etiology of Alzheimer’s disease.191 This was followed by a large number of cross-sectional studies that reported a relationship between homocysteine, and cognitive impairment and dementia.191 These results have been confirmed by both prospective observational studies and meta-analyses, reporting an increased risk of cognitive impairment or dementia in individuals with elevated homocysteine levels.192-195 In several studies the association remains after adjusting for B vitamin status, arguing against vitamin deficiency as the sole mechanism.192, 196, 197 It is possible that the relationship is influenced by another unidentified risk factor or that the risk is due to the combination of several pathways.198, 199
Several clinical trials have been performed to examine the effect of vitamin B supplementation on the levels of homocysteine and cognitive decline. These studies have unquestionably showed the homocysteine lowering effect of B
B12 Folate
Insufficient intake Dietary factors (e.g. malnutrition, vegan diet, alcoholism)
Dietary factors (e.g. malnutrition, alcoholism)
Impaired absorption
or metabolism Pernicious anemia (autoimmune gastritis)
Gastrointestinal disorders (e.g. Crohn's and coeliac disease) Chronic atrophic gastritis High alcohol intake Gastrointestinal surgery Gastrointestinal surgery
Pancreatic disease Tobacco smoking
Inherited disorders Inherited disorders Medications (e.g. proton pump
38
in the next section. It can, in addition to anemia, or as the sole manifestation, give rise to various neurologic symptoms such as polyneuropathy, paresthesia, cognitive impairment, and depression. The exact pathogenic mechanism is not clear, though it is known that deficiency can cause demyelination of central and peripheral neurons.178, 182, 185, 186
1.9.2 FOLATE
Folates is the common name of a family of closely related compounds of water-soluble vitamins. In contrast to vitamin B12, folate is found in many plants such as asparagus, broccoli, green leafy vegetables, and whole grain, but also in animal products such as liver. Folate is absorbed in the proximal part of the jejunum through specific folate transporters. Inside the intestinal cells absorbed forms of folate are converted to 5-methyl-tetrahydrofolate (5-methyl-THF). 5-methyl-THF is the form that circulates in blood where it is either unbound or protein-bound, mainly to albumin.187, 188
The folate cycle is described in figure 8. 5-methyl-THF is a cosubstrate for methionine synthase, the enzyme converting homocysteine to methionine, and is thus part of the methionine cycle. This reaction converts 5-methyl-THF to THF.
In the next step THF accepts a carbon unit from serine forming 5,10-methylene-THF. 5,10-methylene-THF is required for the synthesis of thymidylate and purines, and subsequently important for the synthesis of DNA and RNA. The interruption of this step by the deficiency of folate gives rise to errors in DNA synthesis, the cause of the macrocytic anemia seen in folate deficiency. Even if sufficient levels of folate is available the conversion of 5-methyl-THF to THF is dependent of vitamin B12 and hence vitamin B12 deficiency hampers the folate cycle, a phenomenon called the folate trap, and through this pathway leads to macrocytic anemia. 5,10-methylene-THF converts to dihydrofolate which in turn is converted back to THF. Concomitantly 5,10-methylene-THF is converted to 5-methyl-THF in an irreversible reaction.178, 188, 189
Similar to B12, the classical manifestation of folate deficiency is macrocytic anemia.
It may also give rise to neurological symptoms, such as cognitive impairment and depression.190
39
Table 3. Causes of vitamin B12 and folate deficiency.
1.9.3 HOMOCYSTEINE AND NEUROCOGNITIVE DISEASE The development of cognitive impairment and dementia is multifactorial, where homocysteine may have a contributing role. In the early 1990s two articles were published presenting the hypothesis that homocysteine metabolism might play a role in the etiology of Alzheimer’s disease.191 This was followed by a large number of cross-sectional studies that reported a relationship between homocysteine, and cognitive impairment and dementia.191 These results have been confirmed by both prospective observational studies and meta-analyses, reporting an increased risk of cognitive impairment or dementia in individuals with elevated homocysteine levels.192-195 In several studies the association remains after adjusting for B vitamin status, arguing against vitamin deficiency as the sole mechanism.192, 196, 197 It is possible that the relationship is influenced by another unidentified risk factor or that the risk is due to the combination of several pathways.198, 199
Several clinical trials have been performed to examine the effect of vitamin B supplementation on the levels of homocysteine and cognitive decline. These studies have unquestionably showed the homocysteine lowering effect of B
B12 Folate
Insufficient intake Dietary factors (e.g. malnutrition, vegan diet, alcoholism)
Dietary factors (e.g.
malnutrition, alcoholism)
Impaired absorption
or metabolism Pernicious anemia (autoimmune gastritis)
Gastrointestinal disorders (e.g.
Crohn's and coeliac disease) Chronic atrophic gastritis High alcohol intake Gastrointestinal surgery Gastrointestinal surgery
Pancreatic disease Tobacco smoking
Inherited disorders Inherited disorders Medications (e.g. proton pump
On HIV in the elderly and vitamin B metabolism in HIV infection
40
vitamins, but they have had contradictory results on the effect on cognition.200-205 It has been argued that the lack of effect in many trials is due to inadequate trial design.174, 206
Erika Tyrberg
41
40
vitamins, but they have had contradictory results on the effect on cognition.200-205 It has been argued that the lack of effect in many trials is due to inadequate trial design.174, 206
41
On HIV in the elderly and vitamin B metabolism in HIV infection
42
Aims
Erika Tyrberg
43
2 AIMS
The general aim of this thesis was to describe HIV infection in the elderly, focusing on drug levels, side effects, drug-drug interactions, comorbidities and inflammation, and to investigate the role of homocysteine (as a marker of vitamin B deficiency) in neuronal injury in PLHIV.
The specific aims were:
o To examine drug levels, side effects, adherence, concomitant
medications, drug-drug interactions, and comorbidities in PLHIV aged 65 years or older compared to a group of PLHIV aged 49 years or younger.
o To analyse levels of inflammatory markers in PLHIV aged 65 years or older in individuals with three different ART regimens.
o To explore the relationship of homocysteine levels and signs of neuronal injury in PLHIV.
o To investigate the effect of vitamin B supplementation on signs of neuronal injury in PLHIV with raised levels of homocysteine.
42
Aims
43
2 AIMS
The general aim of this thesis was to describe HIV infection in the elderly, focusing on drug levels, side effects, drug-drug interactions, comorbidities and inflammation, and to investigate the role of homocysteine (as a marker of vitamin B deficiency) in neuronal injury in PLHIV.
The specific aims were:
o To examine drug levels, side effects, adherence, concomitant
medications, drug-drug interactions, and comorbidities in PLHIV aged 65 years or older compared to a group of PLHIV aged 49 years or younger.
o To analyse levels of inflammatory markers in PLHIV aged 65 years or older in individuals with three different ART regimens.
o To explore the relationship of homocysteine levels and signs of neuronal injury in PLHIV.
o To investigate the effect of vitamin B supplementation on signs of neuronal injury in PLHIV with raised levels of homocysteine.
On HIV in the elderly and vitamin B metabolism in HIV infection
44
Study population and design
Erika Tyrberg
45
3 STUDY POPULATION AND DESIGN
The four papers in this thesis are based on three studies. All PLHIV included in the studies attended the Department of Infectious Diseases at Sahlgrenska University Hospital, Gothenburg; South Älvsborg Hospital, Borås; Karolinska University Hospital, Huddinge; or Stockholm South General Hospital, Stockholm. The distribution of study participants is shown in figure 9.
Figure 9. The distribution of study participants in the thesis papers.