Hyperhomocysteinemia and schizophrenia: case control study

Objectives

Homocysteine (Hcys) is a sulphur-containing amino acid that has been widely investigated for its putative role in neuropsychiatric disorders. Elevated plasma homocysteine levels have been associated with schizophrenia. Among other factors, low folate and vitamin B12 levels have been implicated in the increase in homocysteine. The aim of the study was to determine plasma Hcys, folate and vitamin B12, and the frequency and severity of hyperhomocysteinemia in patients with schizophrenia, and to investigate the association between Hcys and clinical features and its relationship with folate and vitamin B12 levels.

Methods

This was a case-control study carried out on 61 (54 males and seven females, mean age = 33.3 ± 9.2) inpatients with chronic schizophrenia according to DSM-IV criteria and 46 (25 males and 21 females, mean age = 45.9 ± 14.2) healthy controls. Most of patients (90.2%) were treated by first generation antipsychotics with a mean daily dosage of 401.6 mg chlorpromazine equivalents. Total homocysteine serum levels were determined quantitatively by fluorescence-polarization immunoassay (FPIA) with an AxSYM analyzer™ (Abbott). Quantitative vitamin B12 and folate serum levels were measured with an Elecsys 2010 analyzer™ (Roche Diagnostics). Differences between patients and controls were examined using a two-way Ancova with gender and diagnosis as independent variables, adjusting for age.

Results

Patients with schizophrenia showed higher plasma Hycs and lower plasma folate than controls (mean = 16.1 μmol/L in patients versus 10.9 μmol/L in controls; P = 0.028 for Hycs and 4.2 μg/L in patients versus 8.2 μg/L in controls; P < 0.001 for folate). Patients and controls did not differ in vitamin B12 levels. Both male and female patients had increased plasma Hcys compared to controls. Hyperhomocysteinemia (Hcys levels > 15 μmol/L) was present in 34.4% of the patients versus 15.2% in controls. The prevalence of moderate hyperhomocysteinemia (Hcys levels: 15–29 μmo/L) was 26.2% and that of intermediate hyperhomocysteinemia (Hcys levels: 30–100 μmol/L) was 8.2%. In patients with schizophrenia, plasma Hcys was not correlated with age (r = 0.07; P = 0.56), duration of illness (r = –0.04; P = 0.78) and did not differ with gender and clinical sub-types. Moreover, plasma Hcys was higher in patients without family history of psychiatric disorders (19.2 μmol/L) versus 12.7 μmol/L in patients with family history of psychiatric disorders (P = 0.032). Concerning therapeutic features, plasma Hcys did not differ with type of antipsychotic and was not related to daily dosage of antipsychotics. A negative correlation was found between plasma Hcys and vitamin B12 levels (r = –0.26; P = 0.04).

Conclusion

These results confirm an increase of Hcys levels in schizophrenic patients and suggest that it is associated with absence of family history of psychiatric disorders and with low vitamin B12 levels. Hyperhomocyteinemia could be related to the pathophysiology of aspects of this illness. Homocysteine should be considered as a factor to consider in monitoring and management of patients with schizophrenia.     

Vitamin B(12) and folate in relation to the development of Alzheimer's disease

OBJECTIVE: To explore the associations of low serum levels of vitamin B(12) and folate with AD occurrence. METHODS: A population-based longitudinal study in Sweden, the Kungsholmen PROJECT: A random sample of 370 nondemented persons, aged 75 years and older and not treated with B(12) and folate, was followed for 3 years to detect incident AD cases. Two cut-off points were used to define low levels of vitamin B(12) (< or =150 and < or =250 pmol/L) and folate (< or =10 and < or =12 nmol/L), and all analyses were performed using both definitions. AD and other types of dementia were diagnosed by specialists according to DSM-III-R criteria. RESULTS: When using B(12) < or =150 pmol/L and folate < or =10 nmol/L to define low levels, compared with people with normal levels of both vitamins, subjects with low levels of B(12) or folate had twice higher risks of developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to 3.5). These associations were even stronger in subjects with good baseline cognition (RR = 3.1, 95% CI = 1.1 to 8.4). Similar relative risks of AD were found in subjects with low levels of B(12) or folate and among those with both vitamins at low levels. A comparable pattern was detected when low vitamin levels were defined as B(12) < or =250 pmol/L and folate < or =12 nmol/L. CONCLUSIONS: This study suggests that vitamin B(12) and folate may be involved in the development of AD. A clear association was detected only when both vitamins were taken into account, especially among the cognitively intact subjects. No interaction was found between the two vitamins. Monitoring serum B(12) and folate concentration in the elderly may be relevant for prevention of AD.     

Antiepileptic Therapy, Folate Deficiency, and Psychiatric Morbidity: A General Practice Survey

The effect of anticonvulsant drugs on folate metabolism and mental symptoms has been investigated extensively in hospital-based studies, but never before in the community or general practice setting. Blood count, serum vitamin B12, red blood cell (RBC), and serum folate were measured in a sample of 82 adult epileptic patients drawn from 5 group practices (14 general practitioners) in southeast London. All patients were receiving antiepileptic medication at the time of examination and were interviewed with a standardized measure of psychopathology. Serum folate values below the lower limit of the normal range (3-15 micrograms/L) were obtained in 9 (10.9%) subjects, and in 50 (60.9%) patients, serum folate concentrations were less than the mean (6.02 micrograms/L) for the whole sample. Macrocytosis was detected in 20 (24.3%) patients. RBC and serum folate levels were significantly correlated with one another, but not with vitamin B12 concentrations. Levels of RBC and serum folate were significantly lower in patients on polytherapy (n = 40) than in those on monotherapy (n = 42); the folate concentrations were also significantly lower in the group with psychiatric morbidity. The association between folate deficiency and affective morbidity was demonstrated for depression but not for anxiety. There was no relationship between serum vitamin B12 and psychiatric disturbance. These findings are discussed in the light of relevant literature regarding the mechanism of action of anticonvulsant drugs in folate depletion and the neuropsychiatric sequelae.     

Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study

OBJECTIVE: It has been hypothesized that adequate concentrations of vitamin B(12) and folate are essential to maintain the integrity of the neurological systems involved in mood regulation, but epidemiologic evidence for such a link in the general population is unavailable. This study examined whether community-dwelling older women with metabolically significant vitamin B(12) or folate deficiency are particularly prone to depression. METHOD: Serum levels of vitamin B(12), folate, methylmalonic acid, and total homocysteine were assayed in 700 disabled, nondemented women aged 65 years and over living in the community. Depressive symptoms were measured by means of the Geriatric Depression Scale and categorized as no depression, mild depression, and severe depression. RESULTS: Serum homocysteine levels, serum folate levels, and the prevalences of folate deficiency and anemia were not associated with depression status. The depressed subjects, especially those with severe depression, had a significantly higher serum methylmalonic acid level and a nonsignificantly lower serum vitamin B(12) level than the nondepressed subjects. Metabolically significant vitamin B(12) deficiency was present in 14.9% of the 478 nondepressed subjects, 17. 0% of the 100 mildly depressed subjects, and 27.0% of the 122 severely depressed women. After adjustment for sociodemographic characteristics and health status, the subjects with vitamin B(12) deficiency were 2.05 times as likely to be severely depressed as were nondeficient subjects. CONCLUSIONS: In community-dwelling older women, metabolically significant vitamin B(12)deficiency is associated with a twofold risk of severe depression.     

Homocysteine in restless legs syndrome

BACKGROUND AND PURPOSE: Total plasma homocysteine (tHcy) may be a risk factor for vascular diseases and is associated with renal failure or deficiency of vitamin B12 or folate. Recently, elevated tHcy concentrations were observed in patients with Parkinson's disease (PD), particularly those under levodopa treatment. Our objective was to determine whether changes in tHcy are also found in patients with restless legs syndrome (RLS) in relation to levodopa treatment and whether folate and vitamins B6 and B12 play a role in RLS. METHODS: In a total of 228 subjects, tHcy and B vitamin status (vitamins B6 and B12, folate) were studied: 97 patients with idiopathic RLS (40 under levodopa therapy), 39 with PD (25 under levodopa therapy), and 92 healthy controls adjusted for age and gender. RESULTS: No significant differences were observed in tHcy levels between RLS patients and controls or between the RLS groups without treatment or with levodopa or dopamine agonist treatment. Mean tHcy was significantly higher in PD patients (13.8 micromol/l) than in either RLS patients (11.7 micromol/l) or controls (11.0 micromol/l; p<0.001). There was an inverse association between tHcy and vitamin B12 in each group. CONCLUSIONS: RLS and, in particular, levodopa treatment in RLS are not associated with hyperhomocysteinemia. Elevated tHcy could, however, be confirmed in PD patients.     

Homocysteine,vitamin B12 and folate levels in Iranian patients with ischemic stroke

Abstract

Objectives: Homocysteine, folate, and some group B vitamins have been proposed as a cause of Cerebro-Vascular Accidents (CVA). We conducted a case-control study to compare the plasma levels of folate, vitamin B12 and homocysteine in Iranian subjects with and without cerebro-vascular accident.

Methods: We recruited 82 patients with ischemic stroke as cases and 60 subjects as controls (using simple nonrandom sampling). Homocysteine was measured by fluorimetric high-performance liquid chromatography. Plasma folate and vitamin B12 levels were measured by an ion-capture method.

Results: Mean plasma level of vitamin B12 in cases and controls were 358.4±290.3 Pg/ml and 369.8±110.4 Pg/ml, respectively which did not show any significant difference. Mean plasma level of folate in cases was significantly lower than the controls (6.8±4.5 ng/ml vs. 12.2±3.0 ng/ml, p=0.001). It was also shown that mean plasma level of total homocysteine in cases was significantly higher than the controls (21.1±9.8 μM/L vs. 13.5±3.2 μM/L, P=0.001). Homocysteine and folate but not plasma B12 had linear relation with age. Male cases had significantly lower Folate and B12 in contrast to women. In addition, male cases had significantly higher Homocysteine level in contrast to women.

Conclusions: Our data shows that the level of homocysteine was higher and the level of folate was significantly lower in patients with ischemic stroke in contrast to controls. Effectiveness of supplementary folate and B 12 in such patients needs further well-structured prospective placebo controlled studies.     

Folate and vitamin B12 levels in levodopa-treated Parkinson's disease patients: their relationship to clinical manifestations, mood and cognition

We tested the hypothesis that mood, clinical manifestations and cognitive impairment of levodopa-treated Parkinson's disease (PD) patients are associated with vitamin B12 and folate deficiency. To this end, we performed this cross-sectional study by measuring serum folate and vitamin B12 blood levels in 111 consecutive PD patients. Levodopa-treated PD patients showed significantly lower serum levels of folate and vitamin B12 than neurological controls, while depressed patients had significantly lower serum folate levels as compared to non-depressed. Cognitively impaired PD patients exhibited significantly lower serum vitamin B12 levels as compared to cognitively non-impaired. In conclusion, lower folate levels were associated with depression, while lower vitamin B12 levels were associated with cognitive impairment. The effects of vitamin supplementation merit further attention and investigation.     

Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report

ABSTRACT: Vitamin B12 is one of the essential vitamins affecting various systems of the body. Reports of psychiatric disorders due to its deficiency mostly focus on middle aged and elderly patients. Here we report a case of vitamin B 12 deficiency in a 16-year old, male adolescent who presented with mixed mood disorder symptoms with psychotic features. Chief complaints were "irritability, regressive behavior, apathy, crying and truancy" which lasted for a year. Premorbid personality was unremarkable with no substance use/exposure or infections. No stressors were present. The patient was not vegetarian. Past medical history and family history was normal. Neurological examination revealed glossitis, ataxia, rigidity in both shoulders, cog-wheel rigidity in the left elbow, bilateral problems of coordination in cerebellar examination, reduced swinging of the arms and masked face. Romberg's sign was present. Laboratory evaluations were normal. Endoscopy and biopsy revealed atrophy of the gastric mucosa with Helicobacter Pylori colonization. Schilling test was suggestive of malabsorbtion. He was diagnosed with Mood disorder with Mixed, Psychotic Features due to Vitamin B12 Deficiency and risperidone 0.5?mg/day and intramuscular vitamin B12 500 mcg/day were started along with referral for treatment of Helicobacter pylori. A visit on the second week revealed no psychotic features. Romberg's sign was negative and cerebellar tests were normal. Extrapyramidal symptoms were reduced while Vitamin B12 levels were elevated. Risperidone was stopped and parenteral Vitamin B12 treatment was continued with monthly injections for 3?months. Follow-up endoscopy and biopsy at the first month demonstrated eradication of H. pylori. He was followed monthly for another 6?months and psychiatric symptoms did not recur at the time of last evaluation. Despite limitations, this case may underline the observation that mood disorders with psychotic features especially with accompanying extrapyramidal symptoms lacking a clear etiology may be rare manifestation of vitamin B12 and/or folate deficiency in children and adolescents and be potentially amenable to treatment.     

Serum vitamin B12, folate,and homocysteine levels and their association with clinical and electrophysiological parameters in multiple sclerosis

Patients with multiple sclerosis (MS) may have low serum vitamin B12 and folate levels and high levels of homocysteine. We aimed to evaluate serum vitamin B12, folate, homocysteine, mean corpuscular volume (MCV), hemoglobin (Hb), and hematocrit (Hct) levels in patients with MS. We examined the relationship between these parameters and age, sex, disease type, age at onset, disease duration, Expanded Disability Status Score, immunoglobulin G (IgG) index, oligoclonal band presence, visual evoked potentials (VEP) and posterior tibial somatosensory evoked potentials (SEP). These parameters were evaluated in 35 patients during an acute attack and compared to data collected from 30 healthy individuals (control subjects). Serum vitamin B12, folate, homocysteine, Hb, and Hct levels and MCV were low in a proportion of patients with MS (20%, 14.3%, 20%, 6.7%, 3.3% and 10% respectively), whereas only vitamin B12 and folate levels were low in only 3.3% of the control subjects. Homocysteine levels were high in 20% of patients with MS but were within normal limits in the control group. Elevated Hct levels were significantly correlated (p < 0.05) with prolonged posterior tibial SEP P1 and P2 latencies compared to the control subjects. Patients with MS who had prolonged VEP and posterior tibial SEP P1 and P2 latencies also had lower vitamin B12 levels compared to patients with normal latencies. Thus, we found a significant relationship between MS and vitamin B12 deficiency, and also demonstrated a relationship between vitamin B12 deficiency, VEP and posterior tibial SEP in MS.     

Relation of higher folate intake to lower risk of Alzheimer disease in the elderly

BACKGROUND: Higher intake of folate and vitamins B6 (pyridoxine hydrochloride) and B12 (cyanocobalamin) may decrease the risk of Alzheimer disease (AD) through the lowering of homocysteine levels. OBJECTIVE: To relate intake of folate and vitamins B6 and B12 to AD risk. DESIGN AND PATIENTS: We followed up 965 persons 65 years or older without dementia at baseline for a mean +/- SD period of 6.1 +/- 3.3 person-years after the administration of a semiquantitative food frequency questionnaire. Total, dietary, and supplement intake of folate and vitamins B6 and B12 and kilocalorie intake were estimated from the questionnaire responses. We related energy-adjusted intake of folate and vitamins B6 and B12 to incident AD using the Cox proportional hazards regression model. MAIN OUTCOME MEASURE: Incident AD. RESULTS: We found 192 cases of incident AD. The highest quartile of total folate intake was related to a lower risk of AD (hazard ratio, 0.5; 95% confidence interval, 0.3-0.9; P=.02 for trend) after adjustment for age, sex, education, ethnic group, the epsilon4 allele of apolipoprotein E, diabetes mellitus, hypertension, current smoking, heart disease, stroke, and vitamin B6 and B12 levels. Vitamin B6 and B12 levels were not related to the risk of AD. CONCLUSIONS: Higher folate intake may decrease the risk of AD independent of other risk factors and levels of vitamins B6 and B12. These results require confirmation with clinical trials.     

Role of vitamin B12, folate, and thyroid stimulating hormone in dementia: A hospital-based study in north Indian population

Background:

Vitamin B₁₂ and folate represent modifiable risk factors for dementia. They may increase the risk of Alzheimer′s dementia (AD) and vascular dementia (VaD) as their deficiency can increase the homocysteine level due to slowed methylation reaction. Homocysteine has a neurotoxic effect that could lead to neurologic disturbances. Hence, it is important to explore the status of serum B₁₂ and folate in AD and VaD to evolve the treatment strategies for the same.

Objectives:

A retrospective study was conducted to assess the levels of vitamin B₁₂, folate, and thyroid stimulating hormone (TSH) in serum and the relationship of these factors, including age and sex to cognitive decline in VaD, AD, and dementia due to other causes (DOC).

Materials and Methods:

Serum vitamin B₁₂, folate, TSH, and total cholesterol were studied in 32 AD patients (mean age: 65 years), 12 VaD patients (mean age: 61 years), 83 DOC (mean age: 65 years), and 127 control subjects (mean age: 49 years). Results: In AD, VaD, and DOC, the levels of vitamin B₁₂ and folate were significantly lower (P < 0.002; 0.026; 0.002 for vitamin B₁₂ and P < 0.000 in all the 3 groups for folate) as compared with the controls. Similarly, TSH levels were significantly lower in AD and DOC (P < 0.008; 0.038) as compared with the controls.

Conclusion:

Vitamin B₁₂ and folate were significantly low in both AD and VaD patients. Hence, B vitamin supplementation should be considered as possible targets for the therapeutic intervention in dementia.     

An investigation of vitamin B12 deficiency in elderly inpatients in neurology department

Objective

To investigate the status of vitamin B12 deficiency in elderly inpatients in the department of neurology.

Methods

A total number of 827 patients in the department of neurology of Shanghai Punan hospital, from March 2007 to July 2008, were employed in the present study. They were 60 years or older, and the average age was 77.1±7.5 years old. All the patients were diagnosed with no severe hepatic or renal dysfunction, without any usage of vitamin B12 during the previous 3 months before the detection. The levels of serum vitamin B12, folate and homocysteine (Hcy) were evaluated. The patients with vitamin B12 deficiency were screened. The resulting symptoms, positive signs of neurological examination, and the neuroelectricphysiological results were compared between patients with or without vitamin B12 deficiency.

Results

Vitamin B12 deficiency was found in 163 patients (19.71% of the total patients), and was more prevalent in female than in male patients, also with increased incidences with aging. Patients with low levels of serum vitamin B12 exhibited higher rate of gastrointestinal diseases, while only 9.82% of the vitamin B12 deficient patients had megaloblastic anemia. Symptoms of vitamin B12 deficiency included unsteadily walking in the darkness and hypopallesthesia, and some chronic diseases such as cerebral ischemia, hypertension, Parkinson’s disease (Parkinsonism), diabetes mellitus and coronary heart disease. Most of the vitamin B12 deficient patients had neuroelectricphysiological abnormalities.

Conclusion

Vitamin B12 deficiency is remarkably common in elderly patients in neurology department, with various and atypical clinical manifestations, and the neurological symptoms are more common than megaloblastic anemia symptoms.     

Vitamin B12, folate,and homocysteine in depression: the Rotterdam Study

OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. METHOD: The authors screened 3,884 elderly people for depressive symptoms. Subjects with positive screening results had psychiatric workups. Folate, vitamin B(12), and homocysteine blood levels were compared in 278 persons with depressive symptoms, including 112 with depressive disorders, and 416 randomly selected reference subjects. Adjustments were made for age, gender, cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.     

Acute dementia with delirium due to vitamin B12 deficiency: a case report

OBJECTIVE: Vitamin B12 (cobalamin) is a key component in the catabolism of monoamines. B12 deficiency is associated with various neuropsychiatric disorders and may be more frequent in psychiatric inpatients. The authors describe a case report of a newly admitted and relatively young patient (52 years old) with organic psychosis secondary to vitamin B12 deficiency. No other overt clinical features of cobalamin deficit were observed. Symptoms were resolved with B12 and folate replacement. The patient's mental status remained stable over the 3 months after the treatment. The authors note that organic mental changes were reversible with B12 replacement. CONCLUSIONS: The authors propose that determination of serum vitamin B12 and folic acid levels should be recommended as routine screening in all new admissions of psychiatric patients regardless of their age or previous state of health.     

Moderate hyperhomocysteinaemia and immune activation in Parkinson's disease

Moderate hyperhomocysteinaemia has been linked to an increased risk for cardiovascular diseases. Increased homocysteine concentrations may follow folate depletion due to insufficient dietary intake of the vitamin, but there is also some indication that immune activation could play a role. In this preliminary study, homocysteine, folate, and vitamin B(12) concentrations were measured in 19 patients with Parkinson's disease, 61-90 years of age, and compared to a healthy control group of similar age and to neopterin concentrations as an indicator of immune activation. A subgroup of patients presented with increased homocysteine and low folate concentrations. Homocysteine levels correlated inversely with vitamins folate and B(12) and positively with neopterin concentrations. Disturbed homocysteine metabolism in Parkinson's disease may be associated with vitamin deficiency and with immune system activation which may underlie folate depletion.     

Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis

BackgroundAlzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment.MethodsWe screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient.ResultsWe identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), whereas nonsignificantly lower levels of zinc (P = .050) and vitamin D (P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD.ConclusionsThe lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management.     

The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events

Total fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 +/- 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 +/- 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 microM in men and >15 microM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78-5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42: 0.84-2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = -0.42 and -0.25) than with the 677CC or CT MTHFR genotype (r = 0).37 and -0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 +/- 206 vs. 408 +/-185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p < or =0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p < or =0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B,2 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.     

Gene--nutrition interactions in coronary artery disease: correlation between the MTHFR C677T polymorphism and folate and homocysteine status in a Korean population

INTRODUCTION: Elevated plasma total homocysteine is a major risk for coronary artery disease (CAD). Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine metabolism; a common C677T mutation in the MTHFR gene results in decreased enzyme activity, and contributes to increased homocysteine levels and decreased folate levels. We investigated the frequency of MTHFR C677T alleles in a Korean population, determined the genotype-specific threshold levels of folate or vitamin B12, and investigated the relationship between the TT genotype and the risk of CAD. MATERIALS AND METHODS: We enrolled a study population of 163 CAD patients and 50 control subjects, and screened the MTHFR C677T polymorphism using real-time PCR with melting point analysis. Levels of plasma homocysteine, folate and vitamin B12 were also determined. We then defined the genotype-specific threshold values of folate and vitamin B12 required to keep homocysteine levels in a normal range for individuals of each MTHFR C677T genotype. RESULTS: The frequency of the TT genotype was 18% in control subjects and 26% in patients group (P>0.05). Individuals homozygous for the TT genotype had significantly elevated homocysteine levels (P<0.05). The genotype-specific folate threshold level was significantly higher in TT individuals than in the CC or CT genotypes. The OR of individuals with low folate status and the TT genotype to estimate the relative risk of CAD was 2.2 and the OR of those with high folate status and the TT genotype was 1.5 (95% CI, 0.5-9.6 and 0.7-3.2, respectively). CONCLUSION: We were able to define a gene-nutrient interaction that shows a higher risk for CAD based on specific threshold folate levels required by different MTHFR C677T genotypes in a Korean population.     

Behavioural and psychological symptoms of Alzheimer type dementia are not correlated with plasma homocysteine concentration

BACKGROUND/AIMS: Vitamin B12 and folate deficiencies have been associated with cognitive impairment and various psychiatric symptoms but not specifically with behavioural and psychological symptoms of dementia (BPSD). A limitation of previous studies in dementia was lack of concurrent homocysteine measurement especially as it may provide a better indicator of tissue activities of these vitamins. This study was designed to clarify whether a relationship exists between plasma homocysteine concentration and BPSD. METHODS: Plasma homocysteine, serum vitamin B12 and folate were measured in 23 Alzheimer's disease (AD) patients with BPSD and 27 AD patients without BPSD as determined through the use of the Neuropsychiatric Inventory (NPI). Blood levels of measured substances were also correlated with individual NPI scores and with cumulative NPI scores for different cluster of symptoms. RESULTS: There was no significant difference (p = 0.956) in the mean plasma homocysteine levels between AD patients with BPSD (17.48 micromol/l) and AD patients without BPSD (17.34 micromol/l). Similarly, there was no significant difference between the two groups in the mean serum B12 (382.61 and 391.60 pg/ml, respectively) and folate (7.95 and 10.02 ng/ml, respectively). Mean levels for both vitamins were well within the laboratory reference range. Neither individual nor cluster NPI scores correlated significantly with plasma homocysteine. CONCLUSION: This study shows for the first time that BPSD are not associated with hyperhomocysteinaemia in Alzheimer dementia. Although previous studies have identified homocysteine as an independent risk factor in AD, the results reported here do not lend weight to an aetiological role for homocysteine specifically in BPSD.     

Intergenotypic variation of Vitamin B12 and Folate in AD: In north indian population

Objectives:

Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including Alzheimer''s disease (AD). With this background, we aim to hypothesize that whether C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene contributes towards the risk of developing AD and its association with vitamin B12 and folate levels.

Materials and Methods:

A case-control study comprising of total 200 subjects, within the age group of 50-85 years. Their blood samples were analyzed for serum folate, vitamin B12 levels, and MTHFR C677T polymorphism by restriction fragment length polymorphism (RFLP).

Results:

The mean plasma levels of vitamin B12 and folate were significantly lower in study group when compared to the control group (P < 0.001). Genotypic and allelic frequency of MTHFR gene in both groups was found to be significant (P < 0.05). The intergenotypic variations of vitamin B12 and folate were found to be significant (P < 0.001).

Conclusion:

We concluded that the subjects with homozygous mutated alleles are more prone to AD and also pointed out the influence of presence/absence of MTHFR T allelic variants on serum folate and vitamin B12 levels.