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ARTICLES: H-X. Wang, Å. Wahlin, H. Basun, J. Fastbom, B. Winblad, and L. Fratiglioni Vitamin B12 and folate in relation to the development of Alzheimer’s disease Neurology 2001; 56: 1188-1194 [Abstract] [Full text] [PDF]

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Reply to Wang and Rieder

Sander Fridman   (8 July 2001)

Reply to Carlos R M Rieder

Hui-Xin Wang   (26 June 2001)

Vitamin B12 and folate in relation to the development of Alzheimer’s disease

Carlos R M Rieder, Daniele Fricke   (26 June 2001)

Reply to Wang and Rieder 8 July 2001
Sander Fridman, psychiatry Forensic Psychiatric Program of the Federal University of Rio de Janeiro - Rio de Janeiro - Brazil Send Correspondence to journal: Re: Reply to Wang and Rieder sander_fridman{at}hotmail.com Sander Fridman	Wang et al question the laboratory criteria for establishing B12 or folate deficiency. The high levels of folate considered to be already pathogenetic (10 and 12nmol/L) are quite alarming since, in our experience, levels quite lower than that are frequent and are generally untreated. On the other hand, B12 researched levels by Wang et al were not accordingly high, since literature indicates peripheral and central neuronal degenerative pathology responsive to B12 supplementation therapy with levels of B12 as high as 350pg/ml. [1] Wang et al reinforce the importance of not expecting enlarged erythrocites before checking for cobalamine and folate levels in patients with neuropsychiatric symptoms in general - not only dementia symptoms. Rieder and Wang's discordant points of view about the meaning of low B12 and folate levels in the further development of Alzheimer Dementia may be due to Wang's overlooked exclusion criteria to DSM-III-R diagnosis of "Primary Dementia of Alzheimer Type" . It is excluded by definition in the presence of low B12 and/or low folic acid. Clinical diagnosis of probable AD is based on the presence of slowly progressive and diffuse cognitive losses together with the improbablity of another possible cause for the dementing process (like B12, folate, B1, Zinc deficit; sedative drugs chronic intoxication; Lues, HIV, etc). Only then does the evaluator indicate the presence of an ongoing underlying Alzheimer neuropathological process. AD is considered by the DSM system as an "all excluded" kind of diagnosis - the last one in the dementia hierarchy. The problem is that the most repeated concept in DSM-III-R, which is present in almost every dignostic category, is that "The mental symptoms cannot be better explained by any other organic disease that affects brain function", which elevates organic mental disorders to the highest diagnostic hierarchy. In DSM-IV, it is the same. However, the DSM system hasn't established--until now--what is considered a minimal organic workup for anyone to seriously answer to that criteria. Reference (1)ROWLAND, LP: Vitamin B12 deficiency, malabsorption, and malnutrition: Merrit's Textbook of Neurology 9th ed. Williams & Wilkins 1995:945-951.
Reply to Carlos R M Rieder 26 June 2001
Hui-Xin Wang Stockholm Gerontology Research Center Stockholm, Sweden Send Correspondence to journal: Re: Reply to Carlos R M Rieder Huixin.wang{at}phs.ki.se Hui-Xin Wang	We thank Rieder and Fricke for their interest in our study. Their letter underlined three main points: 1. Diagnostic difficulty in differentiating Alzheimer’s disease (AD) from dementia due to B12 deficiency; 2. Possible inclusion of vascular cases in the AD group, which may explain the association between vitamin deficiency and neurodegenerative dementia; 3. Inaccuracy of serum B12 level as clinical marker of tissue B12 deficiency. While we agree with Rieder and Fricke on the relevance of the first two points, we are still convinced the low sensitivity and specificity of serum B12 level does not invalidate our results, as was extensively discussed in our article.[1] Regarding the first point, we agree it is difficult to establish a clinical diagnosis of AD in patients with low vitamin B12 or folate levels. Indeed, in the absence of other neurologic or non-neurologic manifestations of vitamin deficiency, only biopsy may help to differentiate AD cases from dementia due to B12 deficiency. With this problem in mind, all the clinical diagnoses in our study were made by physicians that carefully evaluated all causes of dementia and excluded any systemic conditions. Moreover, to improve the quality of our diagnosis, we adopted a double diagnostic procedure, in which two senior clinicians were involved.[1],[6] In response to the second comment, we acknowledge it is more than likely that our clinical-based AD diagnoses are contaminated by mixed cases. However, our findings remained unchanged after taking into account all vascular diseases. Further, neuroimaging would only have partially solved the problem of misclassification of mixed cases in the AD group. Given the observational nature of our study, we cannot identify whether B12 deficiency is involved in the neurodegenerative mechanisms, or if it is acting through vascular mechanisms, which may accelerate the clinical expression of AD. [7] Our population-based study can only suggest that vitamin B12 and folate may be related to the development of clinically-diagnosed AD and dementia. Even when a cut-off of 250 pmol/L was used to define low levels of B12, an increased risk of clinically-diagnosed AD was found. This definitely indicates the importance of monitoring vitamin B12 and folate levels in the elderly. Further observational studies confirming our findings with clinical and experimental investigations exploring these possible mechanisms and underlying the reported associations are warranted. 6 Fratiglioni L, Grut M, Forsell Y, et al. Clinical diagnosis of Alzheimer's disease and other dementia in a population survey. Agreement and causes of disagreement in applying DSM-III-R criteria. Arch Neurol 1992;49:927-932. 7 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997;277:813-817.
Vitamin B12 and folate in relation to the development of Alzheimer’s disease 26 June 2001
Carlos R M Rieder Neurology Service Hospital de Cliniicas de Porto Alegre Porto Alegre, Brazil, Daniele Fricke Send Correspondence to journal: Re: Vitamin B12 and folate in relation to the development of Alzheimer’s disease sandi_moriarity{at}urmc.rochester.edu Carlos R M Rieder, et al.	We read with interest the article by Wang et al. on the association of low serum levels of vitamin B12 and folate with Alzheimer's disease (AD) occurrence.[1] We think that it is difficult to establish a clinical diagnosis of AD in patients with deficiency of vitamin B12 or folate. AD in this situation could be hardly differentiated from other kinds of dementia particularly from dementia associated with B12 deficiency and vascular dementia. Cobalamin (vitamin B12) is a co-factor in several metabolic pathways and its deficiency may be associated with dementia. The authors have controlled the hemoglobin levels. Nevertheless the dementia caused by vitamin B12 deficiency may not be accompanied by anemia. Dementia may be the sole manifestation of cobalamin deficiency.[2] The most important pathway in the nervous system that is adversely affected by cbalamin deficiency involves the conversion of homocysteine to methionine. Demyelination clearly plays a major role in the neuropathogensis of cobalamin deficiency and cognitive changes can occur as a result of central demyelination. [3] Furthermore,it was recently showed that high levels of homocystein are associated with poor word recall in the elderly. [4] High homocysteinemia can be caused by deficiencies of folate or vitamin B12. Another issue to be considered refers to the ifferentiation of vascular dementia. Elevated plasma levels of homocystein have been implanted recently as a risk factor for atherosclerosis and stroke. Homocysteine may be directly toxic to endothelium or thrombogenic. Patients with vascular dementia may be unremarkable. Hachinski Ischemic Scale has been used in this study. However, no imaging study was performed. The cognitive disorder of vascular dementia itself is heterogeneous and may take several different forms. The pleomorphic nature of vascular dementia contributes to diagnostic problems. Although determination of the serum levels of vitamin B12 is the principal diagnostic test for cobalamin deficiency, this test is neither completely sensitive nor specific. We think that further testing for evidence of deficiency should be done in patients with low levels of vitamin B12 in that situation, such as measured of homosysteine and methylmalonic acid levels. We think that the relation between vitamin B12 and folate and the development of Alzheimer's disease is still not yet established. References 1) Wang HX, Wahlin A, Basun H, Fastborn J, Winblad B, Fratiglioni L. Vitamin B12 and folate in relation to the development of Alzheimer's disease. Neurology 2001; 56:1188-1194. 2) Goebels N, Soyka M. Dementia associated with vitamin B12 deficiency: presentation of two cases and review of the literature. J Neuropsychiatry Clin Neurosci. 2000; 12 (3): 389-394. 3) Chatterjee A, Yapundick R, Palmer CA et al: Leukoencephalopathy associated with cobalamin deficiency. Neurology 1996; 46: 832-834. 4) Morris MS, Jacques PF, Rosenberg IH, Selhub J. Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2001; 73: 927- 933.