Your Memory Matters (www.yourmemorymatters.com) is a website for those with questions about early memory loss.

Homocysteine Clinical Studies

  1. Why do homocysteine levels increase?

    Bolander-Gouaille C.
    Springer 2002, 69-117

    Focus on Homocysteine and the Vitamins Involved in its Metabolism, 2nd edition.

  2. Homocysteine and Cognitive Performance in the Framingham Offspring Study: Age Is Important

    Merrill F. Elias, Lisa M. Sullivan, Ralph B. D'Agostino, Penelope K. Elias, Paul F. Jacques, Jacob Selhub, Sudha Seshadri, Rhoda Au, Alexa Beiser and Philip A. Wolf
    American Journal of Epidemiology 2005 162(7):644-653.

    Abstract
    Plasma total homocysteine (tHcy) concentrations are associated with deficits in cognitive performance in persons free from dementia. The extent to which age modifies these associations is in need of further investigation in large, community-based, prospective studies combining the following elements: 1) multiple cognitive tests; 2) statistical adjustment for the role of the vitamin cofactors folate, vitamin B6, and vitamin B12; and 3) adjustment for the presence of risk factors for cardiovascular disease and stroke. Using data collected between 1991 and 2002, the authors investigated the associations between tHcy and multiple measures of cognitive performance in 2,096 dementia- and stroke-free participants of the Framingham Offspring Study, who were stratified into three age groups (40-49 years, 50-59 years, 60-82 years), after findings of statistically significant tHcy-by-age interactions for multiple cognitive measures. Regardless of statistical adjustment for age, sex, gender, the vitamin cofactors, and cardiovascular risk factors, statistically significant inverse associations between tHcy and multiple cognitive domains were observed for individuals aged 60 or more years; no such associations were observed for participants aged less than 60 years. Early preventive interventions may be important, because the inverse association between tHcy and cognitive performance is observed beyond middle age.

  3. Vitamin B12-B6-Folate treatment improves Blood-Brain Barrier function in patients with Hyperhomocysteinaemia and Mild Cognitive Impairment

    Lehmann M, Regland B, Blennow K, and Gottfries CG.
    Dementia and Geriatric Cognitive Disorders 2003;16:145-150.

    Thirty patients had mild cognitive impairment and increased homocysteine levels in serum. On average, they were supplemented orally with a high dose of a vitamin B12-B6-folate combination for 270 days. All patients had normal serum B12 and folate levels at baseline. Cerebrospinal fluid levels of the tau protein (CSF-tau) and the albumin ratio were measured before and after treatment. The serum homocysteine levels were normalised [sic] after treatment. The albumin ratio significantly correlated with vascular risk factors. At baseline, the ratio was higher in the patients in comparison with age-matched controls. After treatment, the ratio was significantly reduced, which may indicate a tightening of the blood-brain barrier. The CSF-tau levels did not change significantly although there was a numeric decline. None of the patients progressed into dementia during the treatment period. When treated with a vitamin B12-B6-folate combination, patients with mild cognitive impairment and hyperhomocysteinemia appear to improve their blood-brain barrier function. They may also stabilise their cognitive status. Further investigations are warranted on the role of blood-brain barrier dysfunction in the pathogenesis of dementia.

  4. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor [excitotoxicity / glycine binding site of N-methyl-D-aspartate receptor / glutamate binding site of N-methyl-D-aspartate receptor / homocyst(e)ine]

    Stuart A. Lipton,, Won-Ki Kim, Yun-Beom Choi, Shanta Kumar, Danielle M. D'Emilia, Posina V. Rayudu, Derrick R. Arnelle, and Jonathan S. Stamler
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 5923-5928, May 1997.

    Abstract
    Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine's neurotoxic (agonist) attributes at 10-100 µM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia

  5. Homocysteine and Cognitive Decline in Healthy Elderly

    Andrew McCaddon, Peter Hudson, Gareth Davies, Alan Hughes, John H.H. Williams, Clare Wilkinson
    Dement. Geriatr. Cogn. Disord. 2001; 12:309-13

    Abstract
    Serum homocysteine is increased, and correlates inversely with cognitive scores, in Alzheimer's disease (AD), vascular dementia and ‘age-associated memory impairment’. Elevated levels might signal accelerated cognitive decline, although this remains to be established. We therefore repeated Mini-Mental State Examinations, together with additional ADAS-Cog assessments, in 32 healthy elderly individuals to determine whether prior homocysteine levels predicted cognitive changes over a 5-year period. Homocysteine predicted follow-up cognitive scores and rate of decline in cognitive performance independently of age, sex, education, renal function, vitamin B status, smoking and hypertension (p < 0.001). Homocysteine predicted word recall (p = 0.01), orientation (p = 0.02) and constructional praxis scores (p < 0.0001). One subject, with the second highest initial homocysteine, had developed probable AD at follow-up. Fasting total serum homocysteine appears to be an independent predictor of cognitive decline in healthy elderly and exerts a maximal effect on spatial copying skills.

    This graph represents technical information presented in McCaddon A. et al. Homocysteine and Cognitive Decline in Healthy Elderly.

  6. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine.

    Nilsson K, Gustafson L, and Hultberg B.
    International Journal of Geriatric Psychiatry. 2001;16:609-614.

    Abstract
    Objectives: To investigate the effect of cobalamin/folate supplementation on cognitive function in elderly patients with dementia.

    Method: The cobalamin/folate status of the patients was evaluated by measuring plasma homocysteine, serum methylmalonic acid, serum cobalamin and blood folate. Thirty-three patients were studied and repeatedly assessed with the Mini-Mental State Examination (MMSE) and 'A short cognitive performance test for assessing memory and attention' (SKT) during vitamin substitution.

    Results: Patients with mild-moderate dementia and elevated plasma homocysteine levels improved clinically with increased test scores after vitamin substitution, while severely demented patients and patients with normal plasma homocysteine levels did not improve clinically.

    Conclusions: Plasma homocysteine may be the best marker for detecting treatable cobalamin/folate deficiency in patients with dementia.

  7. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

    Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA.
    N Engl J Med. 2002 Feb 14; 346(7):476-83     Homocysteine and Risk of Incident Dementia

    Abstract
    Background: In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies.

    Methods: A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier, to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6.

    Results: Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromols per liter, the risk of Alzheimer's disease nearly doubled.

    Conclusions: An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

  8. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study

    Katherine L Tucker, Ning Qiao, Tammy Scott, Irwin Rosenberg and Avron Spiro, III
    American Journal of Clinical Nutrition. 2005;82(3): 627-635.

    Abstract
    Background: Elevated homocysteine concentrations may contribute to cognitive impairment. Most elevations in homocysteine result from inadequate folate, vitamin B-12, or vitamin B-6 intake. It is not clear whether the observed associations between homocysteine and cognitive measures are causal or whether they are due to homocysteine, to independent actions of the B vitamins, or to both.

    Objective: We aimed to assess the individual and independent effects of baseline plasma homocysteine, folate, vitamin B-12, and vitamin B-6 and of dietary B vitamin intakes on 3-y changes in cognitive measures in 321 aging men.

    Design: Participants were from the Veterans Affairs Normative Aging Study. Cognitive function was assessed with the Mini-Mental State Examination and on the basis of measures of memory, verbal fluency, and constructional praxis, which were adapted from the revised Wechsler Adult Intelligence Scale and the Consortium to Establish a Registry for Alzheimer's Disease batteries at 2 time points. At baseline, dietary intakes were assessed with a food-frequency questionnaire, and blood was drawn for the measurement of B vitamins and homocysteine.

    Results: Over a mean 3-y follow-up, declines in constructional praxis, measured by spatial copying, were significantly associated with plasma homocysteine, folate, and vitamins B-6 and B-12 and with the dietary intake of each vitamin. Folate (plasma and dietary) remained independently protective against a decline in spatial copying score after adjustment for other vitamins and for plasma homocysteine. Dietary folate was also protective against a decline in verbal fluency. A high homocysteine concentration was associated with a decline in recall memory.

    Conclusions: Low B vitamin and high homocysteine concentrations predict cognitive decline. Spatial copying measures appear to be most sensitive to these effects in a general population of aging men.

  9. Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

    Jun-Hyun Yoo; Gyu-Dong Choi; Soo-Sang Kang
    Arterioscler Thromb Vasc Biol. 2000; 20:1921-1925
    Distribution of T/T Genotype of MTHFR

    Prevalence of Elevated Homocysteine
    This graph represents technical information presented in: Yoo J-H, Choi G-D, Kang S-S. Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia. Arteriosclerosis, Thrombosis and Vascular Biology 2000; 20:1921-1925.

    Abstract
    Although the major biochemical abnormality due to methylenetetrahydrofolate reductase (MTHFR) deficiency is hyperhomocyst(e)inemia, its pathogenicity appears to involve more than homocysteine toxicity. In patients with severe MTHFR deficiency, a metabolite(s) other than hyperhomocyst(e)inemia also appears to be associated with its clinical manifestation in cerebrovascular disease. To elucidate the specific role of the TT genotype of MTHFR in the development of cerebral infarction with and without cognitive impairment, we determined the prevalence of hyperhomocyst(e)inemia and the C677T genotypes of MTHFR in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 healthy subjects matched for age and sex. Prevalence of hyperhomocyst(e)inemia [homocyst(e)ine 15 µmol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively; P=0.001). In contrast, a higher frequency of MTHFR TT genotype was found only in demented patients compared with nondemented patients and healthy controls (25.2%, 9.8%, and 12.0%, respectively; P=0.01). When the study subjects were divided into normohomocyst(e)inemic and hyperhomocyst(e)inemic groups, the TT genotype was significantly associated with the risk for vascular dementia in the hyperhomocyst(e)inemic group (odds ratio 4.13, 95% CI 2.18 to 7.85; P=0.03) but not in the normohomocyst(e)inemic group. Demented patients with multiple infarcts had a higher frequency of TT genotype (odds ratio 3.13, 95% CI 2.23 to 4.39; P=0.0007), whereas those with a single infarct did not (odds ratio 2.03, P=0.15). In contrast, there was no significant association of the TT genotype with multiple infarcts in hyperhomocyst(e)inemic stroke patients. Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia. Similar to the relationship between homocystinuria due to severe MTHFR deficiency and severe cystathionine ß-synthase deficiency, the TT genotype of MTHFR in hyperhomocyst(e)inemic subjects is differentiated from the cases of the TT genotype without hyperhomocyst(e)inemia or hyperhomocyst(e)inemia without the TT genotype in the development of cerebrovascular disease.