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BRIEF COMMUNICATIONS: P. S. Sachdev, M. Valenzuela, X. L. Wang, J. C.L. Looi, and H. Brodaty Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals Neurology 2002; 58: 1539-1541 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

Perminder Sachdev   (27 December 2002)

Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individual

Stefan Bleich   (27 December 2002)

Letter re Sachdev et al

A. David Smith   (27 June 2002)

Reply to Letter to the Editor 27 December 2002
Perminder Sachdev University of New South Wales and The Prince of Wales Hosptial Randwick NSW Australia Send Correspondence to journal: Re: Reply to Letter to the Editor P.Sachdev{at}unsw.edu.au Perminder Sachdev	The evidence linking elevated homocysteine (Hcy) with brain atrophy is gradually accumulating. To the previously evidence in AD [2] and healthy elderly individuals [1], Bleich and Kornhuber have now added alcohol abuse. Their finding is interesting in itself, as the basis of alcohol-related brain damage is poorly understood. More importantly, it points to a general impact of high Hcy on the brain. The report, however, suffers from the limitation of being cross-sectional, thereby making a causal inference difficult. We cannot also be certain that high Hcy levels are not simply a marker of low levels of folate, vitamin B12 or pyridoxine, deficiencies of which are not uncommon in alcohol dependence [3], and which independently have effects on the brain. It would however be wrong to dismiss this finding, since the potential public health implications are great. High Hcy levels is common in the general population, and these rates go up in a number of disorders including chronic alcoholism [4]. Of equal significance is the fact that interventions to lower Hcy levels are effective and relatively inexpensive [5]. Many cross-sectional and a few longitudinal studies have supported the role of homocysteine as a risk factor for neurodegenerative disease [6], but more prospective studies are needed to confirm the finding. In particular, intervention studies to determine if lowering Hcy levels will lead to reduced rates of cognitive decline and brain atrophy are necessary to base the evidence on a secure footing. References: 1. Sachdev PS, Valenzuela M, Wang XL, Looi JCL, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology 2002;58:1539-1541. 2. Clarke R, Smith D, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-1455. 3. Cravo ML, Camilo ME. Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status. Nutrition 2000;16:296-302. 4. Bleich S, Degner D, Kropp S, Rüther E, Kornhumber J. Red wine, spirits, beer and serum homocysteine. Lancet 2000;356:512. 5. Clarke R, Armitage J. Vitamin supplements and cardiovascular risk review of randomized trials of homocysteine lowering vitamin supplements. Semin Thromb Haemost 2000:26:341-348. 6. Reutens S, Sachdev P. Homocysteine in neuropsychiatric disorders of the elderly. Int J Geriatr Psychiatry 2002;17:859-864.
Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individual 27 December 2002
Stefan Bleich Friedrich-Alexander-University of Erlangen-Nuremberg Germany Send Correspondence to journal: Re: Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individual stefan.bleich{at}psych.imed.uni-erlangen.de Stefan Bleich	We read with interest the study of Sachdev et al. [1] who reported an association between elevated homocysteine levels and brain atrophy in healthy elderly subjects. To our knowledge, this observation is the second report about a linkage between increased homocysteine levels and brain volume reduction. Recently, radiological evidence of temporal atrophy progression in patients with AD has been found to be significant greater among those patients with higher plasma homocysteine levels [2]. In addition to these findings we would like to emphasize the influence of elevated homocysteine levels in chronic alcoholism on alcoholism related brain shrinkage. Chronic alcohol consumption leads, among other lesions, to cortical and subcortical cerebral atrophy (e.g. cerebral white matter, corpus callosum, hippocampal area, cerebellar vermis) [3]. However, the precise mechanisms on which the alcohol-related brain tissue changes are based have yet to be fully explained. There is evidence that chronic alcoholism is associated with hyperhomocysteinemia [4]. In a recent volumetric MRI study including 52 chronic alcoholics we observed that pathological raised levels of plasma homocysteine showed the most significant correlation to brain volume reduction [5]. These results further support the above mentioned observations. The decrease in homocysteine possibly may explain why brain atrophy no longer progresses during abstinence taking into account that homocysteine levels steadily decrease during alcohol withdrawal [4]. Therefore, increased levels of homocysteine in patients with brain atrophy may have important implications for understanding the pathogenesis of neurodegenerative disorders. The results of these studies highlight the need for further research whether neuroprotection against elevated homocysteine levels (e.g. NMDA antagonists) or the lowering of homocysteine (e.g. fortification) will protect patients from neuronal cell loss or brain atrophy. The relationship between increased homocysteine levels, their causes (e.g. common genetic polymorphisms such as methylenetetrahydrofolate reductase mutations) and neurotoxicity warrants further study. References: 1.Sachdev PS, Valenzuela M, Wang XL, Looi JCL, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology 2002;58:1539-1541. 2.Clarke R, Smith D, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12,and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-1455. 3.Harper C. The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? J Neuropathol Exp Neurol 1998;57:101-110. 4.Bleich S, Degner D, Wiltfang J, Maler JM, Niedmann P, Cohrs S, Mangholz A, Porzig J, Sprung R, Rüther E, Kornhuber J. Elevated homocysteine levels in alcohol withdrawal. Alcohol Alcohol 2000;35:351- 354. 5.Bleich S, Bandelow B, Javaheripour K, Müller A, Degner D, Wilhelm J, Havemann-Reinecke U, Sperling W, Rüther E, Kornhuber J. Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism. Neurosci Lett 2002;(in press)
Letter re Sachdev et al 27 June 2002
A. David Smith, Professor of Pharmacology University of Oxford Send Correspondence to journal: Re: Letter re Sachdev et al david.smith{at}pharm.ox.ac.uk A. David Smith	Sachdev et al. [1] report findings of a relationship between measures of brain atrophy and plasma levels of total homocysteine in 36 patients. The power of their study was probably too low to detect a relationship between homocysteine and white matter hyperintensities. Two recent studies have now shown such a relationship [2, 3]. In a prospective study on patients with AD, it was shown that elevated homocysteine levels at baseline were related to a more rapid atrophy of the medial temporal lobe in the following 3 years [4]. In a cohort of normal elderly, the thickness of the medial temporal lobe is inversely related to the level of plasma homocysteine [5]. In the same cohort, the level of homocysteine was inversely related to performance on a cognitive test [6]. Together with other findings, recently reviewed [7], the new results are consistent with elevated homocysteine levels being a risk factor for atrophy of certain brain regions that leads to cognitive decline and to dementia. References [1] Sachdev PS, Valenzuela M, Wang XL,Looi JCL, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals Neurology 2002; 58: 1539-1541. [2] Vermeer SE, van Dijk E, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurol 2002, 51: 285-289. [3] Hogervorst E, Ribeiro HM, et al. Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol 2002, 59:787-793. [4] Clarke R, Smith AD, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998, 55: 1449-1455. [5] Williams JH,Pereira EAC, et al. Hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 2002. In press. [6] Budge M, Johnston C, et al. Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann NY Acad Sci 2000, 903: 407-410. [7] Smith AD. Homocysteine, B vitamins, and cognitive deficit in the elderly. Am J Clin Nutr 2002 75: 785-786.