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Journal of the American College of Nutrition, Vol. 26, No. 3, 272-278 (2007)
Published by the American College of Nutrition

Correlations Between Folate, B12, Homocysteine Levels, and Radiological Markers of Neuropathology in Elderly Post-Stroke Patients

L.-K. Yang, MD, K.-C. Wong, MD, M.-Y. Wu, MS, S.-L. Liao, BS, C.-S. Kuo, MS and R.-F. S. Huang, PhD

Department of Nephrology (L.-K.Y)
Department of Neurology (K.-C.W.)
Department of Clinical Pathology (S.-L.L.), Cardinal Tien Hospital, Hsintien, Taiwan
Department of Nutritional Sciences (M.-Y.W., C.-S.K., R.-F.S.H.) Fu-Jen University, Hsin Chuang, Taiwan, REPUBLIC OF CHINA

Address reprint requests to: Rwei-Fen S. Huang, PhD, Department of Nutritional Sciences, Fu-Jen University, Taiwan, REPUBLIC OF CHINA. E-mail: rweifen{at}mails.fju.edu.tw


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: To investigate serum levels of folate, B12, and total homocysteine (tHcy) in elderly post-stroke patients, and the possible correlations with radiological markers of neuropathology.

Design: Cross-sectional study.

Setting: Department of Neurology, Cardinal Tien Hospital.

Subjects: Eighty-nine elderly post-stroke patients were enrolled for dietary assessment and blood tests. Neuroradiological assessment was done in 62 of these patients.

Main Outcome Measures: Dietary folate and vitamin B12 intakes were evaluated by a 24-h recall system using a semi-quantitative questionnaire. Circulating levels of folate, B12, and tHcy were measured. Magnetic resonance imaging (MRI) or computed tomography (CT) was used for evaluation of brain lesions including infarction and atrophy.

Results: Mean folate and B12 intakes of these post-stroke patients were 69% and 261% of the recommended dietary allowances (RDA), respectively. Inadequate folate levels, defined as serum folate < 6 ng/mL, was noted in 68% of these patients. Hyperhomocysteinemia levels (tHcy ≥15 µmol/L) were observed in 48%. According to tertiles of serum tHcy and folate levels, the rate of brain atrophy, but not brain infarctions, are significantly associated with elevated tHcy (P = 0.0126) and decreased folate levels (P = 0.0273). After adjustments for age, sex, disease status, brain infarctions and carotid stenosis, the odds ratio of brain atrophy was 9.8 (95% CI: 1.7–56.4, P = 0.0101) in the hyperhomocysteinemia group and 9.6 (95% CI: 1.1–81.3, P = 0.0377) in the low folate group (serum folate < 3.0 ng/mL) compared with the group with normal tHcy and folate levels. No significant association was noted between vitamin B12 levels and brain lesions.

Conclusions: Our data shows that folate deficiency and hyperhomocysteinemia are prevalent in elderly post-stroke patients. These two conditions are strongly and independently associated with the development of brain atrophy.

Key words: folate, vitamin B12, homocysteine, dietary intake, brain atrophy, elderly post-stroke patient

Abbreviations: CT = computed tomography • FFQ = Food frequency questionnaire • MRI = magnetic resonance imaging • tHcy = total homocysteine level


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Hyperhomocysteinemia is a known risk factor for atherosclerotic cerebrovascular disease [1, 2]. It has also been implicated in cerebral microangiopathy [3], but the evidence for this is less consistent. Cross-sectional studies have shown that elderly people with hyperhomocysteinemia are at increased risk of developing silent brain infarctions [4, 5, 6]. Hyperhomocysteinemia has also been suggested as a risk factor for brain atrophy in non-demented elderly and even in healthy subjects [7, 8]. A more rapid rate of brain atrophy was observed in patients with Alzheimer's disease and hyperhomocysteinemia [9]. However, the probable correlations between hyperhomocysteneimia and brain infarcts [10], or brain atrophy [5, 11] remain unresolved.

Folate and B12 levels are significant determinants of total homocysteine (tHcy) levels in the elderly [12]. These vitamins play important roles in the maintenance of neurological function [13], yet there is limited evidence that deficiency of these vitamins is associated with the development of brain lesions. Snowdon et al [14] reported that there is a strong association between low levels of serum folate and atrophy of the cerebral cortex in patients with Alzheimer's disease. In a group of psychiatric inpatients, both high tHcy and low folate levels were found to be significantly associated with white matter hyperintensities [15]. Studies regarding the possible correlations between folate or/and vitamin B12 deficiency and atrophy of the neocortex have had conflicting results [16, 17, 18]. Thus, the question how folate and vitamin B12 status may be related to tHcy levels and the risk of brain lesions requires further investigation.

A history of stroke and low serum levels of folate and vitamin B12 are putative risk factors for cognitive decline, vascular dementia and Alzheimer's disease [18–20]. Timely nutritional intervention, particularly in elderly post-stroke patients, may limit further progression to Alzheimer's or vascular dementia. We have previously reported that folate intake among elderly post-stroke patients in Taiwan was lower compared to age- and sex-matched healthy elderly subjects [21]. This study further investigates the correlations between folate and vitamin B12 status, tHcy level, and radiological markers of neuropathology to provide a basis for post-stroke nutritional intervention trials.


   MATERIALS AND METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
A total of 89 elderly (mean age: 69.4 ± 10.6 years) post-stroke patients were recruited from the Department of Neurology of Cardinal Tien Hospital, which has affiliations with Fu-Jen University. Median time interval from occurrence of stroke was 2 years (2.3 ± 1.1 years). Patients with aphasia and/or a concurrent diagnosis of dementia were excluded. Dietary assessment and blood tests were done in all these patients but only 62 patients agreed to undergo MRI or CT. The study protocol was approved by both the Committee on Medical Research of the Cardinal Tien Hospital and the Ethical Review Board of Fu-Jen University. Informed consent was secured from all the participants.

Risk Factors and Dietary Assessment
The patients were asked to complete questionnaires concerning medical history, personal habits, and use of medications. Smoking, alcohol consumption, and intake of vitamin supplements were recorded. Subjects were diagnosed with hypertension with blood pressure levels > 160/90 mm Hg, diabetes with fasting plasma glucose levels greater than 7.0 mmol/L and hyperlipidemia when serum total cholesterol exceeded 5.2 mmol/L. The presence of renal disease was defined by a creatinine level. Hyperhomocysteinemia was defined as serum tHcy levels greater than 15 µmol/L. In accordance with protocols described elsewhere [22], the presence of carotid stenosis was based on MR angiography (MRA) findings and clinical diagnosis was made by a neurologist at the time of recorded stroke.

During scheduled outpatient consultations, experienced dietitians were assigned to assist patients complete a semiquantitative food frequency questionnaire (FFQ) covering the previous 6-month period (recent intake), and the immediately preceding 24 hours (current intake). The FFQ was developed exclusively in our laboratory for assessment of folate and B12 intakes in the Taiwanese population [23]. It has been validated by multiple 24-hour recalls (r = 0.86, P < 0.001) [23] and by plasma folate levels (r = 0.57, P < 0.001) [24].

Blood Biochemical Determinations
Peripheral blood samples were taken after a 12-hour fasting period, chilled and transported to the laboratory, where serum was separated immediately upon arrival. tHcy levels were measured by fluorescence polarization immunoassay (Becton Dickinson, Orangeburg, NY). Serum folate and vitamin B12 levels were determined by commercially available radioimmunoassay kits (Becton Dickinson, Orangeburg, NY).

Measurements of Brain Lesions
Magnetic Resonance Imaging (MRI) was performed with a 1.5-T superconducting magnet (Excite 11.0, GE Medical Systems, Milwaukee, Wis.). A 3-plane scout cut (2D, TR/TE: 54.6/1.7msec, 5mm thick, number of excitations: 1.5) and 5-mm-thick contiguous axial sections through whole brain were performed with Tl-weighted imaging (2D FSE sequence, TR/TE: 600/10.6msec, FOV: 22, 320 x 224 matrix), T2-weighted imaging (2D FSE sequence, TR/TE: 9000/80msec, FOV: 22, 288 x 224 matrix) and FLAIR imaging (2D FSE sequence, TR/TE: 4550/90 msec, TI:2250msec, FOV: 22, 320 x 256 matrix). Computed tomography (CT scan: HiSpeed FXI, GE Medical System, slice thickness: 7 mm, scan diameter: 250 mm, acquisition matrix: 512 x 512, 140 KVp, 200 mA) was used as an alternative method for identification of brain lesions in those patients who were reluctant to undergo MRI. Brain infarction was defined as the presence of focal hyperintensities on T2 weighted images and hypointensities on T1 weighted images, and by at least one spotty area of 3 mm or greater size. Brain atrophy was defined as cortical sulci widening and gyri narrowing as well as enlargement of the brain ventricles, and rating was done by visual inspection of intracranial and total brain volume images of individual patients with reference scans of healthy elderly (aged 65 years or older) controls. The respective diagnoses of brain infarction and global brain atrophy were made by only one neuropathologist in a blinded manner.

Statistical Analysis
Statistical analyses were performed using the Statistical Analysis System (SAS/STAT Version 6.12, SAS Institute, Cary, NC). The Chi-square test was used for categorical variables. For continuous variables, values between groups were examined by the student t test. Differences were considered to be statistically significant whenever P values were < 0.05. The correlations between clinical features, lifestyle, vitamin status, tHcy levels and brain lesions were evaluated using both tHcy and serum folate levels in tertiles and as continuous variables. The means recorded for each parameter across the tertiles were compared by ANOVA (analysis of covariance). Logistic regression models were used to estimate the odds ratio (95% CI) for infarctions and global brain atrophy with respect to tHcy and vitamin status. Non-normally distributed dependent variables were first transformed using a logarithmic function.


   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Clinical and Base-Line Data of Elderly Post-Stroke Patients
Demographic data, lifestyle variables and vitamin intake of these 89 patients are shown in Table 1. No difference was observed with regard to age, BMI, clinical diseases and MRI parameters except that the female patients had a higher incidence of hyperlipidemia, exercised more frequently and were taking vitamin E supplements. In the 62 patients who agreed to undergo MRI or CT, the prevalence of brain atrophy and brain infarction was 39.3% and 88.7%, respectively.


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  		Table 1. Demographic Data, Lifestyle Variables and Vitamin Intake in Post-Stroke Elderly Patientsa

 
Folate, Vitamin B12 Status and tHcy Levels in Elderly Post-Stroke Patients
Table 2 shows that recent and current folate intakes of stroke patients were 279 and 291 µg/d, respectively, which was within 69–72% of dietary reference intakes (DRI: 400 µg folate). Intake of vitamin B12 in these patients was 261% of DRI. No significant difference was noted with regard to dietary folate and B12 intake among the men and women studied. Biochemical data showed that 68% of these post-stroke patients had inadequate folate levels (serum folate < 6 ng/mL) and 48% had hyperhomocysteinemia (tHcy levels ≥ 15 µmol/L). Serum folate and B12 levels also showed no significant sex difference. However, the male patients had significantly higher tHcy levels than the female subjects.


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  		Table 2. Levels of Folate, B12 and tHcy in the Post-Stroke Elderly Patientsa

 
Cerebrovascular Damage in Elderly Post-Stroke Patients with Tertiles of tHcy and Folate Levels
Serum tHcy levels were stratified into high (≥ 15.1 µmol/L), moderate (11.6 to 15.0 µmol/L), and normal (≤ 11.5 µmol/L) categories. As shown in Table 3, male sex (P = 0.035) and folate status (P = 0.0168) were correlated with elevated serum homocysteine levels. The patients with tHcy levels ≥ 15.1 µmol/L had a higher incidence of brain atrophy than those with normal or moderate tHcy levels (p = 0.01). Serum folate levels were classified as adequate (≥ 6.1 ng/mL), marginal (3–6 ng/mL), or low (< 3 ng/mL). Table 4 shows that age (P = 0.001) and tHcy levels (P = 0.003) were correlated with folate status. The patients with low folate levels had a significantly higher incidence of brain atrophy compared to those with marginal or adequate folate levels (P = 0.0273). Folate and tHcy levels were not correlated with the rates of brain infarction and carotid stenosis (Table 3 and 4) or lifestyle profiles (data not shown). Likewise, vitamin B12 status showed no correlation with tHcy and folate levels (Tables 3 and 4), or any brain lesion (data not shown). Neither folate nor B12 intake was correlated with any brain lesions (data not shown).


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  		Table 3. Nutritional Status and Cerebral Vascular Injuries according to Tertiles of tHcy Levels in the Post-Stroke Patients with Neurological Examinationa,b

 

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  		Table 4. Nutritional Status and Cerebral Vascular Injuries according to Tertiles of Serum Folate Levels in the Post-Stroke Patients with Neurological Examinationa,b

 
Odds Ratio of Brain Atrophy according to Serum tHcy and Folate Levels
As shown in Table 5, the odds ratio of brain atrophy associated with high tHcy levels (≥ 15 µmol/L) compared to non-hyperhomocysteinemia levels (< 15 µmol/L) was 9.8 (95% CI: 1.7–56.4, P = 0.0101) after controlling for sex, age (Model A), diseases status (Model B) and cerebrovascular lesions (Model C). After making adjustments for all of the above factors, the odds ratio of brain atrophy was 9.6 (95% CI: 1.1–81.3, P = 0.0377) within the low folate group (serum folate < 3 ng/mL) compared to patients with normal folate levels (Model C). These significant associations were diminished, however, after controlling for folate levels in the patients with hyperhomocysteinemia and for tHcy levels in the low folate group (Model D).


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  		Table 5. Odds Ratios of Brain Atrophy by Serum Homocysteine and Folate Levelsa,b

 

   DISCUSSION
 
Our data confirms previous reports by Lee et al [21] and Huang et al [25] that the majority of post-stroke elderly patients in Taiwan are folate-deficient. More than 50% of our patients had inadequate folate levels (serum folate < 6 ng/mL), although they had normal B12 levels. Low folate levels in these patients may be partially attributed to poor dietary intake since their mean folate intake (291 µg/d) was far below DRI values (Table 2). Levels of tHcy levels in these post-stroke patients with folate malnutrition were significantly higher than in those with normal folate levels (Tables 3, 4), which conforms to the well-documented inverse relationship between folate and tHcy levels [12, 26]. In addition to folate status, male sex was associated with hyperhomocysteinemia in these patients (Table 3). Similar findings were reported in the Framingham Study [12].

Despite the small sample size of this study, our results show that both high tHcy (≥ 15 µmol/L) and low folate (< 3 ng/mL) levels were significantly associated with brain atrophy in elderly post-stroke patients. Our data are highly consistent with earlier reports that elevated tHcy levels and/or low folate status were correlated with brain atrophy across various population sectors [7–9, 14, 16, 17]. Although the exact mechanisms remain unclear, it has been proposed that atherosclerosis of small cerebral vessels or/and neuronal degeneration may contribute to brain atrophy. High tHcy levels have been found to aggravate microvascular disease by impairing endothelial-dependent vasodilatation and increasing the degree of endothelial inflammation [27, 28]. Adjustments made for cerebrovascular injury (carotid stenosis and brain infarcts) did not change the strong association of tHcy and folate status with brain atrophy. Thus, our data suggest that high tHcy and low folate levels may have a direct neurotoxic effect. Independent of its vascular effects, high levels of tHcy have also been reported to increase apoptotic neuronal death [29] and amyloid-beta-peptide toxicity [30]. Folate deprivation and hyperhomocystenemia may induce neurodegeneration by promoting oxidative stress, mitochondrial dysfunction, and apoptotic death [31, 32]. Oxidative stress and aberrations in apoptosis control may contribute to the pathogenesis of premature cell death in a variety of neurological disorders [33]. Our clinical data together with other above-mentioned in vitro studies support the hypothesis that hyperhomocysteinemia and low folate status may directly promote neuronal toxicity which eventually leads to brain shrinkage.

Hyperhomocysteinemia may be possibly related to the incidence of brain infarction in post-stroke patients [19]. However, this study found no such correlation, which may partly be due to the high prevalence of brain infarction in our patients. Our study also has several limitations. First, CT scanning, which is less sensitive in the detection of spotty infarcts less than 1 cm in size, was done in some of the patients reluctant to undergo MRI. Since 89% of the patients with neuroradiological examination were diagnosed to have brain infarction with the help of either MRI or CT scanning, the correct diagnosis may have not been made in only a small proportion of patients (6) with possibly spotty brain infarcts. Thus, this probable underestimation does not alter our conclusions. Second, detection of brain atrophy with MRI was based on visual inspection, which may be observer-dependent. More objective methods such as the brain atrophy index [11] or quantification of brain tissue (brain parenchymal, white matter and grey matter) volumes as fractions of total intracranial volumes by available software [34] are needed for future studies.

In conclusion, our data shows that elderly post-stroke patients are prone to folate deficiency and hyperhomocysteinemia, which both contribute to a higher risk of brain atrophy. Since brain atrophy is considered one of the preclinical markers of Alzheimer's disease, post-stroke patients should undergo periodic neurologic assessment and monitoring of folate and tHcy levels. Whether or not folate supplementation may reduce the risk of brain atrophy in elderly post-stroke patients requires further investigation in longitudinally-designed studies.


   ACKNOWLEDGMENTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Dr. Min-Su Tzeng of Fu-Jen University for her valuable assistance with statistical analysis.


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This work was partly supported by Cardinal Tien Hospital, Taiwan (Grant No. 91-1-2C05).

Both L.-K.Y and K.-C.W. contributed equally to the work.

Received June 4, 2005. Accepted July 25, 2006.


   REFERENCES
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Moller J, Nielsen GM, Tvedegaard KC, Andresen NT, Jorgensen PE: A meta-analysis of cerebrovascular disease and hyperhomocysteinemia.Scand J Clin Lab Invest60 :491 –499,2000 .[Medline]
  2. Austin RC, Lentz SR, Werstuck GH: Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease.Cell Death Differ11 (Suppl 1) :S56 –S64,2004 .
  3. Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M: Homocysteine in cerebral macroangiography and microangiopathy.Lancet353 :1586 –1587,1999 .[Medline]
  4. Matsui T, Arai H, Yuzuriha T, Yao H, Miura M, Hashimoto S, Higuchi S, Matsushita S, Morikawa M, Kato A, Sasaki H: Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people.Stroke32 :1116 –1119,2001 .[Abstract/Free Full Text]
  5. Polyak Z, Stern F, Berner YN, Sela B-A, Gomori JM, Isayev M, Doolman R, Levy S, Dror Y: Hyperhomocysteinemia and vitamin score: correlations with silent brain ischemic lesions and brain atrophy.Dement Geriatr Cogn Disord16 :39 –45,2003 .[Medline]
  6. Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk MO, Hofman A, Clarke R, Breteler MME: Homocysteine, silent brain infarctions, and white matter lesions: The Rotterdam Scan Study.Ann Nuerol51 :285 –289,2002 .
  7. den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, Breteler MMB: Homocysteine and brain atrophy on MRI of non-demented elderly.Brain126 :170 –175,2002 .[Abstract/Free Full Text]
  8. Sachdev P: Homocysteine, cerebrovascular disease and brain atrophy.J Neurol Sci226 :25 –29,2004 .[Medline]
  9. Clarke R., Smith AD, Jobst KA, Refsum H, Sutton I, Ueland PM: Folate, vitamin B12 and serum total homocysteine levels in confirmed Alzheimer's disease.Arch Neurol55 :1449 –1455,1998 .[Abstract/Free Full Text]
  10. Longstroth WT, Katz R, Olson J, Bernick C, Carr JJ, Malinow MR, Hess DL, Cushman M, Schwartz SM: Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons.Arch Neurol61 :67 –72,2004 .[Abstract/Free Full Text]
  11. Sachdev P, Parslow R, Salonikas C, Lux O, Wen W, Kumar R, Naidoo D, Christensen H, Jorm A: Homocsyteine and the brain in midadult life.Arch Neurol61 :1369 –1376,2004 .[Abstract/Free Full Text]
  12. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.JAMA270 :2693 –2698,1993 .[Abstract/Free Full Text]
  13. Morris MS: Folate, homocysteine, and neurological function.Nutr Clin Care5 :124 –132,2002 .[Medline]
  14. Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR: Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study.Am J Clin Nutr71 :993 –998,2000 .[Abstract/Free Full Text]
  15. Scott, TM, Tucker KL, Bhadelia A, Benjamin B, Patz S, Bhadelia R, Leibson E, Price LL, Griffith J, Rosenberg I, Folstein MF: Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders.Am J Geriatr Psychiatry12 :631 –638,2004 .[Medline]
  16. Botez MI, Fontaine F, Botez T, Bachevalier J: Folate-responsive neurological and mental disorders: report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deficiencies.Eur Neurol16 :230 –246,1977 .[Medline]
  17. Martin DC: B12 and folate deficiency dementia.Clin Geriatr Med4 :841 –852,1988 .[Medline]
  18. Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U: Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer disease, and dementia.Am J Clin Nutr80 :114 –22,2004 .[Abstract/Free Full Text]
  19. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro III A: High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Ageing Study.Am J Clin Nutr82 :627 –635,2004 .
  20. Breteler MM: Vascular risk factors for Alzheimer's disease: an epidemiologic perspective.Neurobiol Aging21 :153 –160,2000 .[Medline]
  21. Lee CH, Wong J, Tzeng MS, Huang RFS: Dietary profile of folate intake in long-term post-stroke patients.Nutr Res25 :465 –475,2005 .
  22. Yip PK, Jeng JS, Ng SK, Chang YC, Lee TK, Huang ZS, Chen RC: The stroke and cerebral atherosclerosis study of National Taiwan University Hospital (SCAN): background and methodology.Acta Neurol Taiwan6 :300 –308,1997 .
  23. Lee CH, Lee FY, Wong J, Tzeng MS, Huang RFS: Design of food frequency questionnaire for assessing dietary folate: It's application to study consumption frequency of folate-rich foods in ischemic stroke patients.Nutr Sci J28 :210 –217,2003 .
  24. Kao CS: Relationships between vitamin status, plasma homocysteine and hepatitis in Taiwanese population. Master Thesis,2003 . Department of Nutritional Sciences. Fu-Jen University, Taiwan, ROC.
  25. Huang SY, Chen CI, Chiou HY, Weng PY, Liu PY, Hong CT: The relationship of plasma homocysteine and nutrition factors in acute stroke patients.Nutr Sci J27 :211 –220,2002 .
  26. Jacob RA, Wu MM, Henning SM, Swendseid ME: Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction.J Nutr124 :1072 –1080,1994 .[Abstract/Free Full Text]
  27. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA: Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.Circulation95 :1119 –1121,1997 .[Abstract/Free Full Text]
  28. Hassan A, Hunt BJ, O'Sullivan M, Bell R, D'Souza R, Jeffery S, Bamford JM, Markus HS: Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction.Brain127 :212 –219,2004 .[Abstract/Free Full Text]
  29. Kruman II, Culmsee C, Chan SL, Druman Y, Guo Z, Penix L, Mattson MP: Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.J Neurosci20 :6920 –6926,2000 .[Abstract/Free Full Text]
  30. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, Mattson MP: Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease.J Neurosci22 :1752 –1762,2002 .[Abstract/Free Full Text]
  31. Duan W, Ladenheim B, Cutler RG, kruman II, Cadet JL, Mattson MP: Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease.J Neurochem80 :101 –110,2002 .[Medline]
  32. Ho PI, Ashline D, Dhitavat S, Ortiz D, Collins SC, Shea TB, Rogers E: Folate deprivation induced neurodegeneration: roles of oxidative stress and increased homocysteine.Neurobiol Dis14 :32 –42,2003 .[Medline]
  33. Ekshyyan O, Aw TY: Apoptosis in acute and chronic neurological disorders.Front Biosci9 :1567 –1576,2004 .[Medline]
  34. Chard DT, Griffin CM, Parker GJM, Kapoor R, Thompson AJ, Miller DH: Brain atrophy in clinically early relapsing-remitting multiple sclerosis.Brain125 :327 –337,2002 .[Abstract/Free Full Text]




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