Unilateral Apraxic Agraphia without Ideomotor Apraxia from a callosal lesion in a patient with Marchiafava-Bignami disease.

Apraxic agraphia can be caused by left hemispheric cerebral lesions in the area that contains the spatial representations of the movements required to write, from a lesion in, or connections to, the frontal premotor cortex that converts these spatial representations to motor programs (Exner's area).  A right-handed woman with Marchiafava Bignami disease and lesions of the genu and splenium of her corpus callosum had apraxic agraphia without ideomotor apraxia of her left. A disconnection of Exner's area in the left hemisphere from the right hemisphere's premotor and motor areas may have led to her inability to write with her left hand.

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta.

Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPß, and amyloid ß1-42 (Aß1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aß1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPß were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aß1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aß1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease.

Novel relationships between B12, folate and markers of inflammation, oxidative stress and NAD(H) levels, systemically and in the CNS of a healthy human cohort.

OBJECTIVE: To evaluate the relationship between folate, cobalamin (Cbl), and homocysteine (Hcy), and markers of inflammation and oxidative stress within the periphery and central nervous system (CNS) of a healthy human cohort. METHODS: Thirty-five matched cerebrospinal fluid (CSF) and plasma samples were collected from consenting participants who required a spinal tap for the administration of anaesthetic. Plasma concentrations of Hcy and both plasma and CSF levels of folate, Cbl, nicotinamide adenine dinucleotide (NAD(H)) and markers of inflammation (interleukin-6, IL-6), and oxidative stress (F2-isoprostanes, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and total antioxidant capacity (TAC)) were quantified. RESULTS: In the peripheral circulation, positive associations were observed between plasma folate and Cbl, and plasma TAC (P ≤ 0.01; P ≤ 0.01) and plasma NAD(H) (P ≤ 0.05; P ≤ 0.05) levels, respectively. Plasma folate was inversely associated with plasma Hcy concentrations (P ≤ 0.05); however, no statistically significant relationships were observed between plasma Hcy and plasma markers of inflammation, oxidative stress, or [NAD(H)]. Within the CNS plasma Hcy correlated positively with CSF IL-6 (P ≤ 0.01) and negatively with CSF NAD(H) (P ≤ 0.05) concentrations. An inverse association was observed between CSF folate and CSF levels of IL-6 (P ≤ 0.05). Unexpectedly, a positive association between CSF Cbl and CSF 8-OHdG levels was also found (P ≤ 0.01). DISCUSSION: These results indicate that folate and Cbl concentrations may influence the levels of oxidative damage, inflammation, and NAD(H), both systemically and within the CNS.

The roles of methylenetetrahydrofolate reductase 677C>T and 1298A>C polymorphisms in moyamoya disease patients.

PURPOSE: The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms, which are associated with hyperhomocysteinemia and nitric oxide (NO) deficiency (which is related to atherothrombosis and cerebral ischemia), have not been studied in moyamoya disease. A case-control study was performed to investigate whether the MTHFR 677C>T and 1298A>C polymorphisms contribute to moyamoya disease (MMD). METHODS: One hundred and seven Korean patients with MMD (mean age, 20.85 ± 15.89 years; 66.4 % female) and 232 healthy control subjects (mean age, 23.99 ± 16.16 years; 56.8 % female) were included. Genotyping for the MTHFR 677C>T and 1298A>C polymorphisms and measurements of homocysteine, folate, vitamin B12, and NO in the cerebrospinal fluid (CSF) were performed. The statistical analysis was performed by multivariate linear regression and logistic regression. RESULT: The MTHFR 677CT+TT genotype frequency was significantly increased with early-onset MMD (<10 years) compared with late-onset MMD (≥10 years) (adjusted odds ratio, 3.392; 95 % confidence interval, 1.294-8.893, P = 0.013). The MTHFR 677C-1298C/677T-1298A diplotype (1.71 ± 1.23 arbitrary units) presented significantly lower NO levels in the CSF compared with the 677C-1298A/677C-1298A diplotype (11.40 ± 12.24 arbitrary units). CONCLUSION: The MTHFR 677C>T and 1298A>C polymorphisms have restricted roles in the Korean MMD population. Therefore, further studies involving larger and more heterogeneous cohorts are needed to extend our understanding of the influence of polymorphisms in MTHFR and other thrombophilic genes on MMD.

Biomarkers of folate and vitamin B(12) status in cerebrospinal fluid.

Folate and vitamin B(12) are essential cofactors for the methionine/homocysteine cycle in the brain. These vitamins mediate the remethylation of homocysteine (Hcy), which affects the production of the universal methyl donor, S-adenosylmethionine (SAM), in the brain among other organs. Additionally, increased plasma concentrations of total Hcy (tHcy) are associated with cerebrovascular disease and can compromise the blood-brain barrier. tHcy concentrations in the brain and cerebrospinal fluid become increased in several psychiatric and neurological disorders. Disturbances in the transmethylation pathway indicated by abnormal SAM, S-adenosylhomocysteine or their ratio have been reported in many neurodegenerative diseases, such as dementia, depression or Parkinson's disease. Cobalamin is essential for neuronal generation and its deficiency can cause degeneration of the nervous system. Available data emphasize that deficiency of folate and vitamin B(12) can lead to elevated concentrations of tHcy and disturbed methylation potential in the brain. Therefore, acquired or inherited disorders in these metabolic pathways are associated with brain abnormalities and severe neurological symptoms that are mostly irreversible, even after providing the missing cofactors. This review discusses the relationship between brain and blood levels of key vitamins and metabolites related to one carbon metabolism.

Folate and methylation status in relation to phosphorylated tau protein(181P) and beta-amyloid(1-42) in cerebrospinal fluid.

BACKGROUND: Increased plasma total homocysteine (tHcy) is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained. METHODS: We evaluated concentrations of tHcy, S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), folate, and vitamin B(12) in cerebrospinal fluid (CSF) and plasma or serum from 182 patients with different neurological disorders. We measured concentrations of phosphorylated tau protein (P-tau)((181P)) and beta-amyloid(1-42) in the CSF. RESULTS: Aging was associated with higher concentrations of tHcy and SAH in the CSF, in addition to lower concentrations of CSF folate and lower SAM:SAH ratio. Concentrations of CSF SAH and CSF folate correlated significantly with those of P-tau (r = 0.46 and r = -0.28, respectively). Moreover, P-tau correlated negatively with SAM:SAH ratio (r = -0.40, P <0.001). The association between SAH and higher P-tau was observed in 3 age groups (<41, 41-60, and >60 years). CSF tHcy was predicted by concentrations of CSF cystathionine (beta = 0.478), folate (beta = -0.403), albumin (beta = 0.349), and age (beta = 0.298). CONCLUSIONS: tHcy concentration in the brain is related to age, B vitamins, and CSF albumin. Increase of CSF SAH is related to increased CSF P-tau; decreased degradation of P-tau might be a plausible explanation. Disturbed methyl group metabolism may be the link between hyperhomocysteinemia and neurodegeneration. Lowering tHcy and SAH might protect the brain by preventing P-tau accumulation.

Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid.

BACKGROUND: B-vitamins (folate, B(12)) are important micronutrients for brain function and essential cofactors for homocysteine (HCY) metabolism. Increased HCY has been related to neurological and psychiatric disorders. We studied the role of the B-vitamins in HCY metabolism in the brain. METHODS: We studied blood and cerebrospinal fluid (CSF) samples from 72 patients who underwent lumbar puncture. We measured HCY, methylmalonic acid (MMA), and cystathionine by gas chromatography-mass spectrometry; S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) by liquid chromatography-tandem mass spectrometry; and the B-vitamins by HPLC or immunoassays. RESULTS: Concentrations were lower in CSF than serum or plasma for HCY (0.09 vs 9.4 micromol/L), SAH (13.2 vs 16.8 nmol/L), cystathionine (54 vs 329 nmol/L), and holotranscobalamin (16 vs 63 pmol/L), whereas concentrations in CSF were higher for MMA (359 vs 186 nmol/L) and SAM (270 vs 113 nmol/L; all P <0.05). CSF concentrations of HCY correlated significantly with CSF folate (r = -0.46), CSF SAH (r = 0.48), CSF-albumin (r = 0.31), and age (r = 0.32). Aging was also associated with lower concentrations of CSF-folate and higher CSF-SAH. The relationship between serum and CSF folate depended on serum folate: the correlation (r) of serum and CSF-folate was 0.69 at serum folate <15.7 nmol/L. CSF concentrations of MMA and holotranscobalamin were not significantly correlated. CONCLUSIONS: CSF and serum/plasma concentrations of vitamin biomarkers are significantly correlated. Older age is associated with higher CSF-HCY and CSF-SAH and lower CSF-folate. These metabolic alterations may be important indicators of low folate status, hyperhomocysteinemia, and neurodegenerative diseases.

Priorities in the discovery of the implications of water channels in epilepsy and Duchenne muscular dystrophy.

Folate and vitamin B12 are essential cofactors for the methionine/homocysteine cycle in the brain. These vitamins mediate the remethylation of homocysteine (HCY), which affects the production of the universal methyl donor, S-adenosylmethionine (SAM), in the brain among other organs. Acquired or inherited disorders in these metabolic pathways are associated with brain abnormalities and severe neurological symptoms that are mostly irreversible, even after providing the missing cofactors. This review discusses the relationship between brain and blood levels of key vitamins and metabolites related to one carbon metabolism.

High tumor necrosis factor-alpha [corrected] levels in cerebrospinal fluid of cobalamin-deficient patients.

We studied 14 patients with neurological manifestations of subacute combined degeneration (SCD) and 40 control patients not cobalamin (Cbl)-deficient. The cerebrospinal fluid (CSF) markers of Cbl deficiency (Cbl and total homocysteine [tHCYS] levels) and the CSF levels of tumor necrosis factor (TNF)-alpha and epidermal growth factor (EGF) were measured. Significantly higher levels of tHCYS and TNF-alpha, and significantly lower levels of Cbl and EGF were found in the SCD patients. In human CSF, as in human serum and the rat central nervous system, decreased Cbl concentrations are concomitant with an increase in TNF-alpha and a decrease in EGF-levels. Ann Neurol 2004;56:886-890.

The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease.

There is evidence that increased blood concentrations of homocysteine may be a risk factor for Alzheimer's disease. (E)-4-hydroxy-2-nonenal (HNE) is a neurotoxic product of lipid peroxidation that is increased in the ventricular fluid and brains of patients with Alzheimer's disease. We measured the concentrations of homocysteine, HNE, vitamin B(12) and folate in the plasma of 27 patients with Alzheimer's disease and 25 control subjects. There was a statistically significant increase in the plasma concentration of homocysteine (P < 0.001) and HNE (P < 0.001) in the Alzheimer's disease patients compared to the control group. There was a significant decrease in the plasma concentration of vitamin B(12) (P < 0.001) and folate (P = 0.002) in the Alzheimer's group compared to the controls. There was a significant positive correlation between the plasma concentrations of homocysteine and HNE in the patients with Alzheimer's disease (r = 0.661, P < 0.001). A significant negative correlation was found between the plasma concentration of homocysteine and the plasma concentrations of vitamin B(12) (r = -0.605, P = 0.0006) and folate (r = 0.586, P = 0.001). We also measured the concentrations of homocysteine, HNE, vitamin B(12) and folate in the cerebrospinal fluid (CSF) of 8 patients with Alzheimer's disease compared to 6 control subjects. The concentrations of homocysteine (P = 0.032) and HNE (P = 0.001) were significantly higher in the CSF of Alzheimer's patients than in the control subjects. There were significant positive correlations between the CSF concentrations of homocysteine and HNE (r = 0.924, P = 0.001). There was also a significant positive correlation between the plasma concentration of homocysteine and the CSF concentrations of homocysteine (r = 0.850, P = 0.007) and HNE (r = 0.092, P = 0.002). These results demonstrate that there is a relationship between increased homocysteine concentrations and increased HNE concentrations in Alzheimer's disease.

One-carbon metabolism and other biochemical correlates of cognitive impairment as visualized by principal component analysis.

In the present report, 101 ambulatory elderly patients complaining about cognitive disturbances were investigated using the Mini-Mental State Examination (MMSE). Laboratory investigations, brain imaging, and electroencephalography were performed. Twelve patients were diagnosed with subjective memory complaints (SMC), 32 with mild cognitive impairment (MCI), 43 with dementia of the Alzheimer type (DAT), and 14 with vascular dementia (VAD). Thirty-three percent of the SMC group, 31% of the MCI group, 45% of the DAT group, and 62% of the VAD group had increased serum homocysteine (s-HCY). Principal component analysis of 19 variables showed 3 significant principal components by cross-validation. The cognitive impairment in the patients (MMSE) was explained to 50%. According to the principal component analysis, the population followed two different routes to cognitive impairment: one correlated with disturbance of one-carbon metabolism (cerebrospinal fluid vitamin B12, plasma B12, plasma folate, and s-HCY) and the other correlated with more classic dementia, as marked by cerebrospinal fluid tau, vascular risk factors, atrophy on brain imaging, possession of the apolipoprotein E4 allele, and age. There was poor discrimination between DAT and VAD.

The neurochemical markers in cerebrospinal fluid to differentiate between aseptic and tuberculous meningitis.

In this study, the use of neurochemical markers in patients with aseptic and tuberculous meningitis has been investigated. The cerebrospinal fluid levels of amino acids, nitrite (a metabolite of nitric oxide), vitamin B12 and homocysteine were quantitated in both groups of patients. Among the amino acids, aspartic acid and glutamic acid both excitatory amino acid, GABA, glycine and tryptophan were all significantly increased in both patient groups whereas decreased level of taurine and increased level of phenylalanine were only found in patients with tuberculous meningitis. The levels of nitrite and its precursor arginine were significantly higher in patients with tuberculous meningitis whereas unchanged levels were found in patients with aseptic meningitis. A significantly increased homocysteine level and a decreased level of vitamin B12 were found only in patients with tuberculous meningitis whereas unchanged levels were found in patients with aseptic meningitis. This indicates that patients with tuberculous meningitis are particularly prone to vitamin B12 deficiency resulting into increased level of HC, and involvement of free radical showing the importance of these biological markers for promoting the possibility for the design of therapeutic approach.

Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome.

Twelve outpatients, all women, who fulfilled the criteria for both fibromyalgia and chronic fatigue syndrome were rated on 15 items of the Comprehensive Psychopathological Rating Scale (CPRS-15). These items were chosen to constitute a proper neurasthenic subscale. Blood laboratory levels were generally normal. The most obvious finding was that, in all the patients, the homocysteine (HCY) levels were increased in the cerebrospinal fluid (CSF). There was a significant positive correlation between CSF-HCY levels and fatiguability, and the levels of CSF-B12 correlated significantly with the item of fatiguability and with CPRS-15. The correlations between vitamin B12 and clinical variables of the CPRS-scale in this study indicate that low CSF-B12 values are of clinical importance. Vitamin B12 deficiency causes a deficient remethylation of HCY and is therefore probably contributing to the increased homocysteine levels found in our patient group. We conclude that increased homocysteine levels in the central nervous system characterize patients fulfilling the criteria for both fibromyalgia and chronic fatigue syndrome.

Folate deficiency in cerebrospinal fluid associated with a defect in folate binding protein in the central nervous system.

An adult male patient of Dutch ancestry has a slowly progressive neurological disease characterised by a cerebellar syndrome, distal spinal muscular atrophy, pyramidal tract dysfunction, and perceptive hearing loss. A severe folate deficiency state was found in CSF in combination with a normal serum and red cell folate state. Two unknown abnormal metabolites were present in CSF. The concentration of immunoreactive folate binding protein in CSF was unusually low, whereas the concentration of the protein measured with radioligand (3H-folate) binding was unusually high. The transfer of folate over the choroid plexus seems to be disturbed, potentially reflecting a defect in the choroid plexus folate binder.

Multiple sclerosis and vitamin B12 metabolism.

Multiple sclerosis (MS) is occasionally associated with vitamin B12 deficiency. Recent studies have shown an increased risk of macrocytosis, low serum and/or CSF vitamin B12 levels, raised plasma homocysteine and raised unsaturated R-binder capacity in MS. The aetiology of the vitamin B12 deficiency in MS is often uncertain and a disorder of vitamin B12 binding or transport is suspected. The nature of the association of vitamin B12 deficiency and MS is unclear but is likely to be more than coincidental. There is a remarkable similarity in the epidemiology of MS and pernicious anaemia. Vitamin B12 deficiency should always be looked for in MS. The deficiency may aggravate MS or impair recovery. There is evidence that vitamin B12 is important for myelin synthesis and integrity but further basic studies are required.

Treatment of Alzheimer-type dementia with intravenous mecobalamin.

The efficacy of intravenous mecobalamin in the treatment of Alzheimer-type dementia was evaluated in ten patients using several rating scales. Vitamin B12 levels and unsaturated binding capacities were also measured and compared to the evaluated intellectual function scores. Mecobalamin was shown to improve intellectual functions, such as memory, emotional functions, and communication with other people. Improvements in cognitive functions were relatively constant when the vitamin B12 levels in the cerebrospinal fluid were high. Improvements in communication functions were seen when a certain level of vitamin B12 was maintained for a longer period. There were no side effects attributable to mecobalamin. We conclude that mecobalamin is a safe and effective treatment for psychiatric disorders in patients with Alzheimer-type dementia.