Correspondence

Memantine in Moderate-to-Severe Alzheimer's Disease

N Engl J Med 2003; 349:609-610August 7, 2003

Article

To the Editor:

Reisberg et al. (April 3 issue)1 observed that the N-methyl-D-aspartate (NMDA) antagonist memantine2 appears to be helpful in patients with moderate-to-severe Alzheimer's disease. There is evidence that an increased plasma homocysteine level is an independent risk factor for the development of Alzheimer's disease.3 Homocysteine acts as an agonist at the NMDA receptor, mediates excitotoxicity,4 and disturbs glutamatergic neurotransmission (with associated changes such as an impaired signal-to-noise ratio or long-term potentiation). Furthermore, elevated homocysteine levels are associated with decreased global cognitive performance in patients with Alzheimer's disease3 as well as nondemented elderly persons.5 Homocysteine may act as a mediator of excitatory neurotransmitter output and thus contribute to neurodegeneration6 and cognitive dysfunction, which may be improved by an NMDA antagonist such as memantine. Lowering plasma homocysteine levels through folate administration may help to prevent further neurodegeneration and lead to symptomatic improvement in symptoms of dementia. A combination of memantine or acetylcholinesterase inhibitors and folate may be even more beneficial. Screening patients with Alzheimer's disease for increased homocysteine levels may be particularly important when memantine therapy is established.

Stefan Bleich, M.D.
Jens Wiltfang, M.D.
Johannes Kornhuber, M.D.
Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
stefan.bleich@psych.imed.uni-erlangen.de

6 References

1. 1

   Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333-1334
   Full Text | Web of Science | Medline

2. 2

   Kornhuber J, Bormann J, Retz W, Hubers M, Riederer P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol 1989;166:589-590
   CrossRef | Web of Science | Medline

3. 3

   Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-483
   Full Text | Web of Science | Medline

4. 4

   Prins ND, Den Heijer T, Hofman A, et al. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology 2002;59:1375-1380
   Web of Science | Medline

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   Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:137-146
   CrossRef | Web of Science | Medline

6. 6

   Bleich S, Bandelow B, Javaheripour K, et al. Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism. Neurosci Lett 2003;335:179-182
   CrossRef | Web of Science | Medline

Author/Editor Response

We thank Dr. Bleich and colleagues for their letter and acknowledge their pioneering work in helping to elucidate the mechanism of action of memantine. We agree that glutamatergic excitotoxicity and its effect on the NMDA receptor is a process relevant to many endogenous and exogenous physiologic conditions. We also agree that the full import of the therapeutic approach described in our article — namely, the use of noncompetitive NMDA-receptor antagonism to effect a reduction in glutamate-induced excitotoxicity — requires further study.

Barry Reisberg, M.D.
New York University School of Medicine, New York, NY 10016
barry.reisberg@med.nyu.edu

Rachelle Doody, M.D., Ph.D.
Baylor College of Medicine, Houston, TX 77030

Hans Jörg Möbius, M.D., Ph.D.
Merz Pharmaceuticals, 60318 Frankfurt am Main, Germany

Citing Articles (11)

Citing Articles

1. 1

   P. Alexopoulos, S. Lehrl, T. Richter-Schmidinger, A. Kreusslein, T. Hauenstein, F. Bayerl, P. Jung, T. Kneib, A. Kurz, J. Kornhuber, S. Bleich. (2010) Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults. The journal of nutrition, health & aging 14:4, 283-287
   CrossRef

2. 2

   P. Alexopoulos, S. Lehrl, T. Richter-Schmidinger, A. Kreusslein, T. Hauenstein, F. Bayerl, P. Jung, T. Kneib, A. Kurz, J. Kornhuber, S. Bleich. (2009) Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults. The Journal of Nutrition, Health and Aging
   CrossRef

3. 3

   Marc Muschler, Stefan Bleich. (2008) Einfluss von Alkohol auf Homocystein-Metabolismus und Epigenetik. Psychosomatik und Konsiliarpsychiatrie 2:1, 44-49
   CrossRef

4. 4

   J. Wilhelm, K. Bayerlein, T. Hillemacher, U. Reulbach, H. Frieling, B. Kromolan, D. Degner, J. Kornhuber, S. Bleich. (2006) Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism. Journal of Neural Transmission 113:3, 357-363
   CrossRef

5. 5

   Julia Wilhelm, Nicolas von Ahsen, Helge Frieling, Thomas Hillemacher, Kristina Bayerlein, Dominikus Bönsch, Marc Ziegenbein, Johannes Kornhuber, Stefan Bleich. (2005) Apolipoprotein E4 genotype is not associated with short-term cognition deficits during alcohol withdrawal. Alcohol 37:3, 151-156
   CrossRef

6. 6

   H. Frieling, B. Röschke, J. Kornhuber, J. Wilhelm, K. D. Römer, B. Gruß, D. Bönsch, T. Hillemacher, M. de Zwaan, G. E. Jacoby, S. Bleich. (2005) Cognitive impairment and its association with homocysteine plasma levels in females with eating disorders – findings from the HEaD-study. Journal of Neural Transmission 112:11, 1591-1598
   CrossRef

7. 7

   Stefan Bleich, Marco Carl, Kristina Bayerlein, Udo Reulbach, Teresa Biermann, Thomas Hillemacher, Dominikus B??nsch, Johannes Kornhuber. (2005) Evidence of Increased Homocysteine Levels in Alcoholism: The Franconian Alcoholism Research Studies (FARS). Alcoholism: Clinical & Experimental Research 29:3, 334-336
   CrossRef

8. 8

   Thomas Hillemacher, Udo Reulbach, Kristina Bayerlein, Julia Wilhelm, Dominikus Bönsch, Wolfgang Sperling, Johannes Kornhuber, Stefan Bleich. (2004) Plasma homocysteine concentrations do not influence craving in alcohol withdrawal. Alcohol 34:2-3, 211-215
   CrossRef

9. 9

   Karine Robert, Dominique Santiard-Baron, Jean-Francois Chassé, Evelyne Paly, Joelle Aupetit, Pierre Kamoun, Jacqueline London, Nathalie Janel. (2004) The neuronal SAPK/JNK pathway is altered in a murine model of hyperhomocysteinemia. Journal of Neurochemistry 89:1, 33-43
   CrossRef

10. 10

    (2003) Current awareness in geriatric psychiatry. International Journal of Geriatric Psychiatry 18:12, 1149-1156
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11. 11

    Stefan Bleich, Johannes Kornhuber, Anselm G.M. J??nemann. (2003) Homocysteine in Primary and Secondary Open-Angle Glaucoma. Journal of Glaucoma 12:6, 498-499
    CrossRef