Published online before print March 27, 2003, doi: 10.1161/01.STR.0000065102.16626.54
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(Stroke. 2003;34:833.)
© 2003 American Heart Association, Inc.
Letters to the Editor |
Immune Activation to Underlie Moderate Hyperhomocysteinemia in Stroke and Dementia?
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Innsbruck, Austria
To the Editor:
With interest we read the article by McIlroy et al,1 in which moderate hyperhomocysteinemia was described in patients with vascular dementia, stroke, and Alzheimer’s disease (AD) in comparison with control groups. The authors suggest that mild hyperhomocysteinemia may significantly increase the risk for vascular dementia, AD, or stroke. Korczyn2 argues against this conclusion, suggesting other causes like endothelial dysfunction in consequence of oxidative stress to be important as contributing factors for dementia. Likewise, hyperhomocysteinemia could be a consequence of stroke and dementia rather than its cause.
In earlier studies in patients with AD, deficiency of B-vitamins folate and vitamin B12 was associated with elevated plasma homocysteine concentrations.3–5 Thus, diminished availability of essential cofactors in the homocysteine-methionine-metabolism appears to be responsible for elevated homocysteine concentrations. Usually insufficient dietary intake is considered as the cause for the deficiency of these vitamins,3–5 and folate deficiency can cause several neurologic and psychiatric symptoms, especially in the elderly.6
There seems to exist a link between oxidative stress involved in the pathogenesis of dementia and stroke and the depletion of B-vitamins. Since activation of immunocompetent cells like T-lymphocytes and macrophages is associated with overwhelming production of oxidizing compounds, immune activation is a major cause of oxidative stress.7 Oxidative stress in scope with chronic immune activation could therefore lead to the depletion of antioxidants including oxidation-sensitive vitamins like folate and vitamin B12. Methyl-tetrahydrofolate and cobalamine are important cofactors in the biochemical conversion of homocysteine and both are readily oxidized.7,8 Chronic immune activation has been discussed to be crucially involved in the pathogenesis of AD,9 and, eg, elevated concentrations of immune activation markers like neopterin, itself being a pro-oxidant by increasing the oxidative potential of reactive oxygen species, have been found in dementia and AD,10 but also in stroke.11
Oxidative stress resulting from immune activation indeed could represent the cause for moderate hyperhomocysteinemia. This relationship is well in line with the observation by McIlroy et al1 and the alternative interpretation by Korczyn,2 and it would also fit to the observation that not only supplementation with antioxidant vitamins but also treatment with anti-inflammatory drugs has some capacity to lower homocysteine levels and also reduce the risk for dementia.12,13 In addition to supplementation with B-vitamins, also antioxidant and anti-inflammatory strategies could therefore compensate for enhanced B-vitamin consumption in consequence of immune activation and effectively prevent the progression of cognitive impairment.
References
1. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke. 2002; 33: 2351–2356.
2. Korczyn AD. Homocysteine, stroke, and dementia. Stroke. 2002; 33: 2343–2344.
3. Levitt AJ, Karlinsky H. Folate, vitamin B12, and cognitive impairment in patients with Alzheimer’s disease. Acta Psychiatr Scand. 1992; 86: 301–305.[Medline] [Order article via Infotrieve]
4. Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, Fuchs D. Hyperhomocysteinemia in dementia. J Neural Transm. 2000; 107: 1469–1474.[CrossRef]
5. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology. 2001; 56: 1188–1194.
6. Reynolds EH. Folic acid, ageing, depression, and dementia. Br Med J. 2002; 324: 1512–1515.
7. Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake? Clin Chem Lab Med. 2001; 39: 691–694.[CrossRef][Medline] [Order article via Infotrieve]
8. McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology. 2002; 58: 1395–1399.
9. Rogers J, Webster S, Lue LF, Brachova L, Civin WH, Emmerling M, Shivers B, Walker D, McGeer P. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging. 1996; 17: 681–686.[CrossRef][Medline] [Order article via Infotrieve]
10. Leblhuber F, Walli J, Demel U, Tilz GP, Widner B, Fuchs D. Increased serum neopterin concentrations in patients with Alzheimer’s disease. Clin Chem Lab Med. 1999; 37: 429–431.[CrossRef][Medline] [Order article via Infotrieve]
11. Grau AJ, Reis A, Buggle F, Al-Khalaf A, Werle E, Valois N, Bertram M, Becher H, Grond-Ginsbach C. Monocyte function and plasma levels of interleukin-8 in acute ischemic stroke. J Neurol Sci. 2001 15; 192: 41–47.[CrossRef][Medline] [Order article via Infotrieve]
12. Esposito E, Rotilio D, Di Matteo V, Di Giulio C, Cacchio M, Algeri S. A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes. Neurobiol Aging. 2002; 23: 719–735.[CrossRef][Medline] [Order article via Infotrieve]
13. Breitner JC. Inflammatory processes and antiinflammatory drugs in Alzheimer’s disease: a current appraisal. Neurobiol Aging. 1996; 17: 789–794.[CrossRef][Medline] [Order article via Infotrieve]
Department of Geriatric Medicine, Queen’s University of Belfast, Belfast, Northern Ireland
Response
We thank Schroecksnadel et al for their interest in our article and feel that their letter raises a few interesting points. Although it appears to be true that diminished availability of essential co-factors in the metabolism of methionine homocysteine pathway are responsible for elevated homocysteine concentrations, insufficient dietary intake is not the cause as this was allowed for in our study.1 However, unlike the conclusions reached by Schroecksnadel et al, we do not believe that immune activation represents the cause of raised homocysteine levels.
It has recently been reported that homocysteine actively inhibits the activation of endothelium by the pro-inflammatory cytokine tumor necrosis factor (TNF).2 Activation of endothelial cells is a prerequisite for the recruitment of leukocytes to sites of evolving inflammation.3 Pro-inflammatory cytokines such as TNF and interleukin-1 rapidly induce activation of nuclear factor 
B (NF B) and binding to its target DNA resulting in up-regulation of NF B-dependent genes, such as E-selectin, vascular cell adhesion molecule-1 or chemokines including macrophage chemoattractant protein-1 and IL-8.4,5 Thus since raised homocysteine levels inhibit immune activation, the statement that oxidative stress resulting from immune activation may represent the cause of moderate hyperhomocysteinemia may require modification. In addition, in a recent report Mezzano et al6 considered patients with chronic renal failure and observed that systemic inflammation which is closely associated with augmented oxidative stress is a major cardiovascular risk factor and that the total plasma homocysteine is completely unrelated to these events.
The exact nature of the influence of raised homocysteine in risk for stroke and dementia remains controversial. Further studies are needed to clarify links between inflammatory mechanisms, aminothiol pathways and endothelial function and as we advocated in our original article1 the only way to determine the nature of the risk or otherwise conferred by homocysteine is to initiate a large placebo controlled study into the effects of folate and B vitamin supplementation on rates of stroke and dementia.
References
1. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia and Alzheimer’s disease in Northern Ireland. Stroke. 2002; 33: 2351–2356.
2. Roth J, Goebeler M, Ludwig S, Wagner L, Kilian K, Sorg C, Harms E, Schulze-Osthoff K, Koch H-G. Homocysteine inhibits tumor necrosis factor-induced activation of endothelium via modulation of nuclear factor-b activity. Biochem Biophys Acta. 2001; 1540: 154–165.[Medline]
[Order article via Infotrieve]
3. Gimbrone MA. Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis. Am J Cardiol. 1995; 75: 67b–70b.[Medline] [Order article via Infotrieve]
4. Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood. 1994; 84: 2068–2101.
5. May JM, Gosh S. Signal transduction through NF-B. Immunol Today. 1998; 19: 80–88.[CrossRef][Medline]
[Order article via Infotrieve]
6. Mezzano D, Pais EO, Aranda E, Panes O, Downey P, Ortiz M, Tagle R, Gonzalez F, Quiroga T, Caceres MS, et al. Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia. Kidney Intern. 2001; 60: 1844–1850.[CrossRef][Medline] [Order article via Infotrieve]
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