Homocysteine, hopelessness, rumination, affective temperaments, and clinical course in patients with bipolar disorder-1.

PURPOSE: This study aimed to explore the associations between homocysteine, rumination, affective temperaments, clinical features, and hopelessness in bipolar disorder-1 (BD-1). MATERIALS AND METHODS: In total, 57 euthymic patients with BD-1 and 57 healthy controls were included. The Beck Hopelessness Scale (BHS), Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A), and Ruminative Responses Scale Short Form (RRS-SF) were administered. Homocysteine, folate, and vitamin B12 levels were measured. RESULTS: The BHS total (p = 0.047), TEMPS-A irritable (p = 0.007), and TEMPS-A cyclothymic (p= 0.001) scores were significantly higher than the control group in the BD-1 group. Hyperhomocysteinemia (HHcy) was found in 33.3% of the patients (n = 19). In the HHcy group, age of onset of disease (p = 0.020) was significantly lower than the non-HHcy group in patients. Previous suicide attempt number was significantly correlated with scores of reflective pondering, brooding, and global rumination in BD-1 (p Ë‚ 0.05). Except for hyperthymic temperament, all types of affective temperaments were correlated with the scores of RRS-SF brooding (p Ë‚ 0.05) in the BD-1 group. The RRS-SF brooding scores significantly correlated with the BHS total scores (r = 0.263, p < 0.05); the TEMPS-A hyperthymic (ß = -0.351, p = 0.001) and TEMPS-A irritable (ß = 0.536, p < 0.001) scores significantly predicted the BHS total scores in the BD-1 group. CONCLUSIONS: The findings may lead clinical efforts and future clinical trials to explore and intervene in related sources and presentations of BD-1's adverse consequences.

B vitamin supplementation improves cognitive function in the middle aged and elderly with hyperhomocysteinemia.

OBJECTIVE: An intervention study was performed to determine if supplement containing folic acid, vitamin B6, and vitamin B12 could improve cognitive function and lower homocysteine in middle-aged and elderly patients with hyperhomocysteinemia. METHODS: One hundred and four participants with hyperhomocysteinemia were recruited in Tianjin, China, aged 55-94 years old. Fifty-seven individuals with hyperhomocysteinemia were included in the intervention group (vitamin B group, which received 800 µg/day of folate, with 10 mg of vitamin B6 and 25 µg of vitamin B12) and 47 patients in the placebo group. The endpoint was the improvement in cognitive function as evaluated by Basic Cognitive Aptitude Tests (BCATs). All parameters were measured before and after the treatment period of 14 weeks. RESULTS: The BCAT total score and four sub-tests scores (digit copy, Chinese character rotation, digital working memory, and recognition of meaningless figure) of BCAT at 14 weeks significantly increased only for the vitamin B group. Serum total homocysteine (tHcy) levels significantly decreased in the intervention group, while serum concentrations of folate, vitamin B6, and vitamin B12 significantly increased in the intervention group. CONCLUSION: The results demonstrated that supplement containing folate, vitamin B6, and vitamin B12 in middle-aged and elderly patients with hyperhomocysteinemia could improve their cognitive function partly and reduce serum tHcy levels.

[The influence of hyperhomocysteinemia on monoaminoergic systems of hypothalamus and hippocampus of female rats at aging].

The data presented have shown the different effect of hyperhomocysteinemia (induced by 0,12-0,15 mg of methionine loading per os during 30 days) on monoamines content in hypothalamus and hippocampus of young (6-7 month) and old (20-22 month) female rats. It has been established that the level of catecholamines (noradrenaline, dopamine), 5 oxitryptamine and 5 oxyindolacetic acid in hypothalamic areas responsible for synthesis and secretion of gonadoliberin (medial preoptic area and medial eminence with arcuate nuclei) is considerable less in old animals compared with young ones. These data are in agreement with the low content of gonadoliberin found by us in medial eminence with arcuate nuclei. It has been also shown the decreased level of monoamines level in hippocampus of old rats, which does not depend on methionine loading. However in hippocampus of young animals hyperhomocysteinemia induced a noticeable reduction of noradrenaline and 5 oxyindolacetic acid, which can lead to weakening of animal's cognitive function.

Homocysteine levels in schizophrenia patients newly admitted to an acute psychiatric ward.

OBJECTIVE: After the discovery of 'homocystinuria syndrome', many studies have suggested that high blood levels of homocysteine may be associated with schizophrenia. The aim of this study was to analyse the association between hyperhomocysteinaemia and schizophrenia. METHODS: In a population of inpatients suffering from exacerbated schizophrenic disorders (N=100), we evaluated homocysteine levels the day after their admission to an acute psychiatric ward and compared it with that of a non-patient control group (N=110), matched for age and gender. We statistically analysed the correlation between homocysteine levels and selected variables: gender, age, years of illness and number of previous psychiatric admissions as well as Brief Psychiatric Rating Scale, Positive Negative Syndrome Scale and Global Assessment Functioning (GAF) Scores. RESULTS: We observed elevated homocysteine levels (an increase of 7.84 µM on average per patient) in 32% of the patients, but we did not find any statistically significant difference between the homocysteine levels of our patients and controls. Hyperhomocysteinaemia presented a positive statistically significant correlation with years of illness (p<0.005) and a negative statistically significant correlation with GAF score (p<0.001), but not with other clinical variables. CONCLUSIONS: Hyperhomocysteinaemia, which occurred in our schizophrenia patients with poor social and relational functioning after many years of illness, could represent an effect of altered lifestyle due to psychosis, but not a specific marker for schizophrenia.

Cognitive and neurochemical alterations in hyperhomocysteinemic rat.

Accumulating data have shown that the level of serum homocysteine in patients with mild cognitive impairment, vascular dementia and Alzheimer's disease is higher than normal while the underlying mechanism is not fully understood. Here, a hyperhomocysteinemic rat model was made by maintaining rats on a diet high in methionine. The cognitive behavior, level of monoamine neurotransmitters in brain homogenates and brain-derived neurotrophic factor (BDNF) in cerebral spinal fluid (CSF) were compared between high-methionine diet and control group. The high-methionine diet group presented longer mean latency of escape and lesser time in target quadrant in morris maze test, lower level of serotonin and dopamine in cortex homogenates and lower level of BDNF in CSF. Together, our findings provide evidence that hyperhomocysteinemia could cause alterations of monoamine and neurotrophic factor, which might be further pathogenetic mechanisms underlying the cognitive deterioration.

[Hyperhomocysteinemia and schizophrenia: case control study]. / Hyperhomocystéinémie et schizophrénie : étude cas-témoin.

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.

A randomized placebo-controlled trial of using B vitamins to prevent cognitive decline in older mild cognitive impairment patients.

BACKGROUND & AIMS: Mild cognitive impairment (MCI) patients are at risk of cognitive decline, while elevated serum homocysteine is also associated with cognitive impairment. Thus, older people with MCI and hyperhomocysteinemia may be under greater risk of cognitive decline. We therefore performed a randomized trial of homocysteine-lowering by B vitamins supplementation to prevent cognitive decline in older MCI patients with elevated serum homocysteine. METHODS: 279 MCI outpatients aged ≥65 years with serum homocysteine ≥10.0 µmol/L were randomly assigned to take either methylcobalamin 500 µg and folic acid 400 µg once daily, or two placebo tablets for 24 months. All subjects were followed up at 12 monthly intervals. The primary outcome was cognitive decline as defined by an increase in clinical dementia rating scale (CDR) sum of boxes (CDR_SOB). The secondary outcomes were global CDR, memory Z score, executive function Z score and Hamilton depression rating scale (HDRS) score. RESULTS: The clinical characteristics between two groups were well matched, except that the supplement group had better executive function. The supplement effectively lowered serum homocysteine (mean 13.9 ± sd 3.5 µmol at baseline to 9.3 ± 2.4 µmol/L at month 24). At month 24, there was no significant group difference in CDR_SOB or any secondary outcomes (mean changes in CDR_SOB 0.36 versus 0.22 in supplement and placebo groups respectively). At month 12, the supplement group significantly improved in executive function and had lower HDRS score (P = 0.004 and 0.012 respectively). Group difference was significant for HDRS, but borderline significant for executive function. (P = 0.01; 0.06 respectively) These effects were not significant at month 24. Subgroup analysis showed that aspirin use had significant interaction with B supplements in CDR_SOB at month 24 (Beta 0.189, P = 0.005). CONCLUSIONS: Vitamin B12 and folic acid supplementation did not reduce cognitive decline in older people with MCI and elevated serum homocysteine, though the cognitive decline over two years in placebo group was small. The supplement led to a significant reduction in depressive symptoms at month 12, though this effect was not sustained. Aspirin use had a negative interaction effect on cognitive functioning with B supplements. CLINICAL TRIAL REGISTRATION: Centre for Clinical Research and Biostatistics (CCRB) Clinical Trials Registry: CUHK_CCT00373.

Impact of Hyperhomocysteinemia and Different Dietary Interventions on Cognitive Performance in a Knock-in Mouse Model for Alzheimer's Disease.

BACKGROUND: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer's disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. METHODS: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-ß (Aß) plaque deposition. RESULTS: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified Aß plaque deposition in 35-week-old AppNL-G-F mice. CONCLUSION: Despite prominent Aß plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress.

Hydrogen sulfide (H2S) is endogenously produced from sulfur containing amino acids, including homocysteine and exerts neuroprotective effects. An increase of homocysteine during pregnancy impairs fetal growth and development of the offspring due to severe oxidative stress. We analyzed the effects of the H2S donor-sodium hydrosulfide (NaHS) administered to female rats with hyperhomocysteinemia (hHcy) on behavioral impairments and levels of oxidative stress of their offspring. Rats born from females fed with control or high methionine diet, with or without H2S donor injections were investigated. Rats with maternal hHcy exhibit increased levels of total locomotor activity and anxiety, decreased muscle endurance and motor coordination, abnormalities of fine motor control, as well as reduced spatial memory and learning. Oxidative stress in brain tissues measured by activity of glutathione peroxidases and the level of malondialdehyde was higher in rats with maternal hHcy. Concentrations of H2S and the activity and expression of the H2S generating enzyme-cystathionine-beta synthase-were lower compared to the control group. Administration of the H2S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral together with biochemical studies will add to our knowledge about homocysteine neurotoxicity and proposes H2S as a potential agent for therapy of hHcy associated disorders.

Low-dose alcohol ameliorated homocysteine-induced anxiety-related behavior via attenuating oxidative stress in mice.

Recent studies showed that homocysteine (Hcy) levels were obviously elevated in patients with anxiety, furthermore, oxidative stress and inflammation were closely linked with Hcy-related damage. Despite alcohol exposure has differential effects on different forms of anxiety, the role of alcohol on anxiety-related behavior induced by high Hcy levels is still not entirely clear. The present study investigated the protective potential of low-dose alcohol against homocysteine-induced anxiety-related behavior and explored the possible underlying mechanisms. Mice were administered intragastrically with methionine (2.0 g/kg/day) or alcohol (0.6 g/kg/day). After 21 days of administration, the anxiety-related behavior was evaluated through open field (OF) and elevated plus maze (EPM) tests, and the variations of oxidative stress and inflammation levels were measured. The results of OF and EPM tests showed that the anxiety-related behavior in mice was prevented by alcohol treatment. Alcohol lowered the elevated serum Hcy levels and alleviated the damage of hippocampal tissues in hyperhomocysteinemia (HHcy) mice. Meanwhile, the superoxide dismutase (SOD) activity of the hippocampal tissues enhanced, and the malondialdehyde (MDA) concentration of the hippocampal tissues and the serum interleukin-1ß (IL-1ß) level decreased. In addition, after administering alcohol, the increase of superoxide dismutase 1 (SOD1), heme oxygenase 1 (HO-1) protein expression and the decrease of IL-1ß protein expression were also detected in HHcy mice hippocampal tissues. Taken together, low-dose alcohol significantly ameliorated the Hcy-induced anxiety-related behavior in mice, which might be related to SOD1 and HO-1 upregulation and IL-1ß downregulation.

Evaluation of hyperhomocysteinemia prevalence and its influence on the selected cognitive functions in patients with schizophrenia.

There is evidence that hyperhomocysteinemia may be associated with the development of schizophrenia and cognitive impairment. Therefore, the aim of this study was to analyze the relationship between cognitive functions and normal homocysteine concentrations vs. hyperhomocysteinemia in schizophrenia patients before and after supplementation with vitamins B6, B12 and folate. An 8-week prospective, non-randomized study enrolled 122 adult patients with schizophrenia (67F/55M, mean age 43.54 ±â€¯11.94 years). Homocysteine concentrations were measured in all individuals and afterwards hyperhomocysteinemia patients (n = 42) were divided into two subgroups: treated with oral vitamins supplementation (B6 - 25 mg/d, B12 - 20 µg/d, folate - 2,5 mg/d) (n = 22) and without supplementation (n = 20). The assessment of schizophrenia symptoms severity in study group was performed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functions were evaluated using the Stroop test and the Trail Making Test (TMT). We observed a higher prevalence of hyperhomocysteinemia in schizophrenia patients (34.4%) in comparison to the general population. Individuals with schizophrenia and coexisting hyperhomocysteinemia had worse performance on the Stroop and the TMT tests as well as higher PANSS scores. In these patients, supplementation with vitamins effectively decreased the homocysteine concentrations to the normal values, however there was no statistically significant improvement in the PANSS and cognitive test scores, except a significant decrease in the number of the Stroop test errors. We conclude that significant results obtained in this study show that there is a relationship between homocysteine blood concentration and schizophrenia severity. Moreover, homocysteine concentration lowering might be beneficial in schizophrenia patients with hyperhomocysteinemia in terms of cognitive functions improvement.

Homocysteine, folate and cognition in a large community-based sample of elderly people--the 3C Dijon Study.

BACKGROUND: Hyperhomocysteinemia is associated with an increased risk of cognitive impairment in the elderly. Recent studies suggest that folate level may also influence the course of cognitive decline. OBJECTIVE: We performed the cross-sectional analysis of the relationship between homocysteine and folate levels and cognitive performances in a population-based study including 3,914 subjects aged 65 years and older. METHOD: Subjects had an evaluation of their cognitive level using five neuropsychological tests. A Cognitive Summary Score was computed as the sum of each of the 5 cognitive tests score standardized. Relations of folate and homocysteine levels with cognition were first studied separately in a covariance analysis. Stratified analyses were also performed because of interaction between folate and homocysteine in relation to cognition. RESULTS: Subjects in the higher quartile of homocysteine (high homocysteine group) and subjects in the lower quartile of folate (low folate group) had consistently lower cognitive performances in all tests. When stratified on folate level, high homocysteinemia was associated with lower cognitive performances only in subjects with a low folate level. CONCLUSION: In this large population-based sample of elderly people, the association between high homocysteinemia and decreased cognition was only seen in participants with low folate levels.

Hypoalbuminemia and not hyperhomocysteinemia as a risk factor for dementia in hemodialysis patients.

BACKGROUND: The most common causes of morbidity and mortality in uremic patients are cardiovascular disease and central nervous system dysfunction. However, the exact causes of dementia in uremic patients remain unclear. This study attempted to determine which risk factors are associated with dementia in hemodialysis patients. METHODS: In total, 147 chronic uremic patients receiving regular hemodialysis treatment were recruited. Data for risk factors regarding cardiovascular disease and dementia, such as hypertension, diabetes mellitus, smoking, age, illiteracy, serum levels of albumin, cholesterol, triglycerides, and homocysteine, and liver function, were recorded. The Mini-Mental Status examination was used to assess mental function, and the Hachinski ischemic scale was applied to differentiate among dementia types. The diagnosis of dementia was based on criteria from the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. RESULTS: Twenty-six patients were diagnosed as manifesting dementia. Of all patients with dementia, 21 had a Hachinski score of 0 to 4, and 5 had a score of 7 to 10. In a multiple logistic regression analysis, low serum albumin and illiteracy were significantly associated with dementia. However, no difference existed between the two groups in terms of homocysteine levels. CONCLUSIONS: This study demonstrated that uremic patients were prone to nonvascular dementia. We conclude that hypoalbuminemia and not hyperhomocysteinemia is a risk factor for dementia in hemodialysis patients.

Prevalence and clinical-demographic correlates of hyperhomocysteinemia in inpatients with bipolar disorder in a Han Chinese population.

Recent studies have reported that hyperhomocystinemia (HHcy) is highly prevalent in patients with bipolar disorder (BD), placing them at greater risk of cardiovascular disease and possibly serving as a disease biomarker. However, the correlation of HHcy with demographic or clinical parameters is not well known. In this study, we examined the prevalence of HHcy and its association with these parameters in a sample of Chinese BD patients. Fasting plasma homocysteine (Hcy) levels were determined in 198 BD inpatients and 84 healthy controls. HHcy was defined when Hcy concentration exceeded 15.0µmol/L. Affective symptomatology was assessed by the Young Mania Rating Scale, Hamilton Depression Rating Scale and the Clinical Global Impressions severity scale. Compared to healthy controls, BD patients had a significantly higher prevalence (34.85% vs. 19.05%) of HHcy and a higher absolute level of homocysteine. Logistic regression analysis demonstrated that BD patients with HHcy were more likely to be male, have elevated BMI, more frequent treatment on lithium but less on valproate. These results suggest that Chinese inpatients with bipolar disorder have a higher rate of HHcy than the general population, and those at greatest risk are male, have an elevated BMI, and take more lithium but less valproate therapy.

Neuroprotective Effect of Hydrogen Sulfide in Hyperhomocysteinemia Is Mediated Through Antioxidant Action Involving Nrf2.

Homocysteine (Hcy) is a sulfur-containing amino acid derived from methionine metabolism. Elevated plasma Hcy levels (> 15 µM) result in a condition called hyperhomocysteinemia (HHcy), which is an independent risk factor in the development of various neurodegenerative disorders. Reactive oxygen species (ROS) produced by auto-oxidation of Hcy have been implicated in HHcy-associated neurological conditions. Hydrogen sulfide (H2S) is emerging as a potent neuroprotective and neuromodulator molecule. The present study was aimed to evaluate the ability of NaHS (a source of H2S) to attenuate Hcy-induced oxidative stress and altered antioxidant status in animals subjected to HHcy. Impaired cognitive functions assessed by Y-maze and elevated plus maze in Hcy-treated animals were reversed on NaHS administration. Increased levels of ROS, lipid peroxidation, protein carbonyls, and 4-hydroxynonenal (4-HNE)-modified proteins were observed in the cortex and hippocampus of Hcy-treated animals suggesting accentuated oxidative stress. This increase in Hcy-induced oxidative stress was reversed following NaHS supplementation. GSH/GSSG ratio, activity of antioxidant enzymes viz; superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were decreased in Hcy-treated animals. NaHS supplementation, on the otherhand, restored redox ratio and activity of antioxidant enzymes in the brains of animals with HHcy. Further, NaHS administration normalized nuclear factor erythroid 2-related factor 2 expression and acetylcholinesterase (AChE) activity in the brain of Hcy-treated animals. Histopathological studies using cresyl violet indicated higher number of pyknotic neurons in the cortex and hippocampus of HHcy animals, which were reversed by NaHS administration. The results clearly demonstrate that NaHS treatment significantly ameliorates Hcy-induced cognitive impairment by attenuating oxidative stress, improving antioxidant status, and modulating AChE activity thereby suggesting potential of H2S as a therapeutic molecule.

Ginkgo biloba Extract EGb761 Attenuates Hyperhomocysteinemia-induced AD Like Tau Hyperphosphorylation and Cognitive Impairment in Rats.

BACKGROUND: Ginkgo biloba extract EGb761 has shown the neuroprotective effects on Alzheimer's disease (AD) through the protection against the Aß-induced neurotoxicity. However, it is not completedly clear whether EGb761 attenuates tau hyperphosphorylation, another of the most prominent mechanisms underlying the pathology of AD. METHODS: we employed hyperhomocysteinemia (HHcy) to mimic AD like pathological alterations and memory deficits in rats as model, and injected EGb761 with or after HHcy injection as prevention and treatment, injected saline as control. We measured the status of oxidative damage and spatial and learning memory in rats. Then we detected the level of memory-related proteins, tau phosphorylation and the level and activity of tau kinase (GSK-3ß) and phosphatase (PP2A) by Western blotting and Immunohistochemistry. RESULTS: We found that EGb761 could significantly antagonize HHcy-induced oxidative damage, recover PP2Ac and GSK3ß activities deregulated by HHcy. Furthermore, tau was hyperphosphorylated at Thr231, Ser262, Ser396, and Ser404, most common PP2Ac and GSK3ß targeted sites in the hippocampus and prefrontal cortex of HHcy rats, whereas EGb761 recovered the tau phosphorylation at those sites. Behavioral tests revealed that EGb761 rescued HHcy-induced spatial reference memory deficit and upregulated the expression of synapse-associated protein PSD95 and synapsin-1. CONCLUSION: EGb761 might be a promising drug to treat AD through its anti-oxidative activity and decreasing tau hyperphosphorylation besides the protection against the Aß-induced neurotoxicity.

Impact of impaired fasting glucose and other metabolic factors on cognitive function in elderly people.

AIM: The present study was undertaken to evaluate the impact of impaired fasting glucose (IFG), insulin resistance (IR) and hyperhomocysteinaemia (Hhcy) on cognitive function (CF) in a sample of non-diabetic elderly subjects. METHODS AND RESULTS: One hundred and eighty-two non-diabetic subjects, aged > or = 65 years, without signs of previous stroke were included in the study. CF was evaluated by the Mini Mental State Examination (MMSE) score, corrected for age and education. Since diagnostic criteria for IFG have been recently lowered from 110 to 100 mg/dl, subjects were categorized according to old (IFG1997) and new (IFG2003) criteria. IR and Hhcy were defined by the upper quartile of insulin (11.0 UI/L) and Hcy (18.6 micromol/L) distribution, respectively. The frequency of IFG1997, Hhcy, and IR, but not of IFG2003, showed a linear trend across tertiles of MMSE (p<0.001). The odds ratio (95% CI) for impaired CF (MMSE<24.3) was 9.08 (2.97-27.74) for IFG1997, 3.66 (1.28-10.45) for Hhcy, 2.83 (1.25-6.37) for IR and 1.32 (0.61-2.89) for IFG2003. CONCLUSIONS: Our study shows that IFG1997, Hhcy and IR are powerful metabolic markers of impaired CF among elderly people.

B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial.

BACKGROUND: Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients. DESIGN: The study was a longitudinal ancillary of the FAVORIT trial, a randomized, placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinically stable kidney transplant recipients with elevated tHcy. PARTICIPANTS: 584 participants from 18 sites across North America. INTERVENTION: The intervention consisted of a daily multivitamin containing high-doses of folate (5.0 mg), vitamin B12 (1.0 mg) and vitamin B6 (50 mg). The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 (0 mg folate; 2.0 µg vitamin B12; 1.4 mg vitamin B6). MEASUREMENTS: Annual neuropsychological assessment for up to 5 years (mean 3.3 years) using a standardized test battery. Efficacy was analyzed on an intention-to-treat basis using end-of-trial data. Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations. RESULTS: At baseline, cognitive impairment was common with 61% of participants falling more than one standard deviation below published norms for at least one cognitive test. Fewer than 1% of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However, 44.6% had plasma B6 concentrations < 30 nmol/L. At follow-up, processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls (p≤0.05). There was no interaction between baseline tHcy, B-vitamin status and treatment on the cognitive outcomes. CONCLUSIONS: High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy. Since nearly all participants were folate and vitamin B12 sufficient at baseline, the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined.

Homocysteine concentrations in the cognitive progression of Alzheimer's disease.

OBJECTIVES: Hyperhomocysteinemia in Alzheimer's disease (AD) is widely reported and appears to worsen as the disease progresses. While active dietary intervention with vitamins B12 and folate decreases homocysteine blood levels, with promising clinical outcomes in Mild Cognitive Impairment (MCI), this so far has not been replicated in established AD populations. The aim of the study is to explore the relationship between hyperhomocystenemia and relevant vitamins as the disease progresses. METHODS: In this longitudinal cohort study, 38 participants with mild to moderate AD were followed for an average period of 13months. Plasma folate, vitamin B12 and homocysteine concentrations were measured at baseline and at follow-up. Dietary intake of B vitamins was also measured. Spearman's correlations were conducted by homocysteine and B vitamin status. RESULTS: As expected, cognitive status significantly declined over the follow-up period and this was paralleled by a significant increase in homocysteine concentrations (p=0.006). However, during this follow-up period there was no significant decline in neither dietary intake, nor the corresponding blood concentrations of vitamin B12/folate, with both remaining within normal values. Changes in blood concentrations of B vitamins were not associated with changes in homocysteine levels (p>0.05). CONCLUSION: In this study, the increase in homocysteine observed in AD patients as the disease progresses cannot be solely explained by dietary and blood levels of folate and vitamin B12. Other dietary and non-dietary factors may contribute to hyperhomocysteinemia and its toxic effect in AD, which needs to be explored to optimise timely intervention strategies.

Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease.

BACKGROUND: Hyperhomocysteinemia is associated with cerebral small vessel disease (SVD). We examined the relationship between homocysteine and 1) volumetric measure of white matter change (WMC), 2) silent brain infarcts, 3) cerebral atrophy on MRI and 4) cognition on a consecutive cohort of patients with stroke associated with SVD. SUBJECTS AND METHODS: Fifty-seven patients consecutively admitted to the Acute Stroke Unit in a university hospital due to stroke associated with SVD were recruited and assessed three months after the stroke. Non-fasting homocysteine was obtained. Using MRI, the number of infarcts, volume of WMC and cerebral atrophy were measured. General cognitive functions were assessed using the Mini Mental State Examination and Alzheimer's disease Assessment Scale. Mattis Dementia Rating Scale - Initiation/Perseveration subset was used to assess executive cognitive functions. RESULTS: Hyperhomocysteinemia (> or = 14.88 micromol/L) significantly accounted for the volume of WMC on MRI in a multivariate stepwise regression model (adjusted R(2)=0.058, p <0.05) after adjustment for age and folate level. Patients in the highest quartile of WMC volume had significantly higher levels of homocysteine than those in lowest quartile (p <0.001). No significant relationship was found between homocysteine and silent brain infarcts, cerebral atrophy and performance on psychometric tests. CONCLUSION: Hyperhomocysteinemia is associated with volumetric measure of WMC among patients with SVD. The role of homocysteine in the development of silent brain infarcts and cerebral atrophy as previously reported cannot be ascertained in this study. No direct relationship was found between homocysteine and cognitive functions.