Neurology -- Correspondence for Miller et al., 58 (10) 1471-1475

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Correspondence published:

Reply to Letter to the Editor: Joshua W. Miller, Ralph Green, Dan M. Mungas, Bruce R. Reed and William J. Jagust (17 July 2002)

Homocysteine, vitamin B6, and vascular disease in AD patients: Barbara Borroni, Chiara Agosti, Anna Franca Panzali, Monica Di Luca and Alessandro Padovani (17 July 2002)

Reply to Letter to the Editor 17 July 2002

Joshua W. Miller
UC Davis Medical Center Sacramento CA,
Ralph Green, Dan M. Mungas, Bruce R. Reed and William J. Jagust
Send Correspondence to journal:
Re: Reply to Letter to the Editor

jwmiller{at}ucdavis.edu Joshua W. Miller, et al.

The data presented by Borroni et al. replicate our finding that elevated plasma homocysteine concentrations are associated with vascular disease, but not AD. [1] It is interesting to note that the same conclusion was reached in our study and that of Borroni et al. despite a clear difference between the two study samples in the range of homocysteine values observed. In our study, mean homocysteine levels for the study sample subgroups ranged from 9.3 to 13.8 ľmol/L, while in the Borroni et al. study they ranged from 13.8 to 18.0 ľmol/L. The likely explanation for this difference is folic acid fortification, which has been instituted in the United States and has successfully lowered homocysteine levels in the general population. [3] As far as we know, folic acid fortification has not been instituted in Italy, the location of the Borroni et al study. Consistent with this supposition is that Borroni et al. found that the only significant independent predictors of homocysteine levels were vascular disease and folate. In our study, folate was not a significant predictor of homocysteine levels because overall folate status of our study sample was relatively high and homocysteine is only expected to become elevated when folate status is below a certain threshold. [4]
Nonetheless, the consistent finding in both studies that vascular disease, but not AD, is an independent predictor of homocysteine levels has potentially important implications. It has recently been reported that elevated homocysteine levels predicted dementia and AD incidence in the Framingham Heart Study population. [2] Though this suggests that homocysteine is a causative factor in dementia and AD, it remains possible that homocysteine is simply a marker for vascular disease and that vascular disease is the important risk factor for dementia. This implies that blood homocysteine levels become elevated as a consequence of vascular disease. A mechanism by which this may occur has been postulated. [5]
Two final points: First, as reported by Borroni et al., we too did not observe a significant association between homocysteine and dementia severity in our AD patients as indicated by Mini-Mental State Examination scores. Though this could be viewed as substantiating the conclusion that there is no direct relationship between homocysteine and AD, as suggested by Borroni et al., it must be noted that both our study and theirs were cross-sectional in design. It is difficult to ascertain in such a design the length of time a person has had dementia, certainly a critical factor in considering the severity of the disease. Last, Borroni et al. have mistakenly said that we found an association between pyridoxal-5'- phosphate (vitamin B6) and homocysteine in our study sample, which we in fact did not. What we did find was that low B6 status conferred a significant odds ratio for AD independent of homocysteine and vascular disease. We are currently trying to replicate this finding and to determine the ramifications of low B6 status in AD patients.
References:
1. Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology 2002;58:1471- 1475.
2. Thomas T, Thomas G, McLendon C, et al. Beta amyloid mediated vasoactivity and vascular endothelial damage. Nature 1996; 380:168-171.
3. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454.
4. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-2698.
5. Brattstrom L, Wilcken DEL. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000;72:315-23.

Homocysteine, vitamin B6, and vascular disease in AD patients 17 July 2002

Barbara Borroni
University of Brescia Italy,
Chiara Agosti, Anna Franca Panzali, Monica Di Luca and Alessandro Padovani
Send Correspondence to journal:
Re: Homocysteine, vitamin B6, and vascular disease in AD patients

bborroni{at}inwind.it Barbara Borroni, et al.

We read with interest the article by Miller et al. about plasma homocysteine (Hcy) levels in Alzheimer Disease (AD) patients. [1] They found that high Hcy levels are not associated with AD whereas both in AD and controls they are related to vascular disease. These conclusions fit well with our on-going study carried out on a consecutive series of AD patients and controls. One hundred-six AD patients and 186 age- and sex- matched controls have been enrolled so far. All subjects performed a standardized clinical and laboratory work-up including plasmatic levels of vitamin B12, folate, and Hcy. Both patients and controls were classified into two subgroups (vascular vs non vascular) according to the presence of hypertension, diabetes, history of stroke or TIA, cerebrovascular lesions on CT, myocardial infarction, angina, congestive heart failure, coronary artery disease or peripheral vascular disease. No significant difference in Hcy levels was found between AD patients and controls (16.2ą8.3 vs 17.1ą9.1; p=0.37), whereas within each group vascular subgroups showed higher Hcy levels. In particular, within the AD group there was a significant difference for Hcy levels between vascular AD and non-vascular AD (18.0ą8.0 vs 13.8ą7.9, p<.02), but not for vitamin B12 or folate. Through a multivariate analysis entering vascular condition, Mini-Mental State Examination scores, demographic and laboratory variables, only vascular disease (b=.258) and folate (b=.210) were found to independently predict Hcy levels (R=.16, p<.02). [2]
In agreement with the findings by Miller et al., these results support the strong association between Hcy values and vascular pathology in AD, thus arguing against the claim of a direct relationship between Hcy and AD. [3] This view is further substantiated by the lack of association between Hcy levels and dementia severity. Moreover, Hcy levels are likely dependent on nutritional factors as shown by the association with folate in our series and with pyridoxal-5-phosphate in the sample reported by Miller et al. We agree with the authors that further studies are required to elucidate the role of Hcy in AD progression, as vascular damage is likely to contribute to the course of dementia. The recent literature has focused the attention on vascular changes related to AD as a consequence of Ab peptide toxicity and its deposition. [4] The published article underlines the need to understand which measures of vascular damage are involved in AD pathology and how they relate with concomitant vascular risk factor(s) whereby dementia course could be faster.
References:
1. Miller JW, Green R, Mungas DM, et al. Homocysteine,su Vit B6, and vascular disease in AD patients. Neurology 2002; 58:1471-1475.
2. Refsum H, Ueland PM, Nygard O, et al. Homocysteine and cardiovascular disease. Annu Rev Med 1998; 49:31-62.
3. Seshadri S, Beisei A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimers disease. N Engl J Med 2002; 346:476-483.
4. Thomas T, Thomas G, McLendon C, et al. Beta amyloid mediated vasoactivity and vascular endothelial damage. Nature 1996; 380:168-171.