Andrew McCaddon

Total serum homocysteine in senile dementia of Alzheimer type

Objective. The main hypothesis was that subtle vitamin B12 deficiencies occur more commonly in senile dementia of Alzheimer type (SDAT) than in healthy elderly individuals, and may be revealed by elevated total serum homocysteine (tHcy). A subsidiary hypothesis was that such deficiencies would be nutritionally independent as determined by retinol binding protein (RBP).

Homocysteine and cognitive decline in healthy elderly.

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

The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases

Abstract Hyperhomocysteinemia (HHcy) is related to central nervous system diseases. Epidemiological studies show a positive, dose-dependent relationship between plasma total homocysteine (tHcy) concentration and neurodegenerative disease risk. tHcy is a marker of B-vitamin (folate, B12, B6) status. Hypomethylation, caused by low B-vitamin status and HHcy, is linked to key pathomechanisms of dementia; B-vitamin supplementation could potentially reduce neurological damage. In retrospective studies, the association between tHcy and cognition is impressive; there is also evidence that tHcy-lowering treatment could be effective in primary and secondary stroke prevention. Increased tHcy and low serum folate occur in patients with Parkinsons disease, especially those receiving L-dopa. There is also an association between HHcy and multiple sclerosis, and between B-vitamin status and depression. Studies also confirm a causal role for tHcy in epilepsy, and certain anti-epileptics enhance HHcy. B-vitamin status should be optimized by ensuring sufficient intake in patients with neuropsychiatric diseases. HHcy occurs commonly in the elderly and can contribute to age-related neurodegeneration. Treatment with folic acid, B12 and B6 lowers tHcy. For secondary and primary prevention from several neuropsychiatric disorders, it seems prudent to actively identify deficient subjects and ensure sufficient vitamin intake. Clin Chem Lab Med 2007;45:1590–606.

A novel role for vitamin B12: Cobalamins are intracellular antioxidants in vitro

Oxidative stress is a feature of many chronic inflammatory diseases. Such diseases are associated with up-regulation of a vitamin B(12) (cobalamin) blood transport protein and its membrane receptor, suggesting a link between cobalamin and the cellular response to inflammation. The ability of cobalamin to regulate inflammatory cytokines suggests that it may have antioxidative properties. Here we show that cobalamins, including the novel thiolatocobalamins N-acetyl-l-cysteinylcobalamin and glutathionylcobalamin, are remarkably effective antioxidants in vitro. We also show that thiolatocobalamins have superior efficacy compared with other cobalamin forms, other cobalamins in combination with N-acetyl-l-cysteine (NAC) or glutathione (GSH), and NAC or GSH alone. Pretreatment of Sk-Hep-1 cells with thiolatocobalamins afforded robust protection (>90% cell survival) against exposure to 30 microM concentrations of the pro-oxidants homocysteine and hydrogen peroxide. The compounds inhibited intracellular peroxide production, maintained intracellular glutathione levels, and prevented apoptotic and necrotic cell death. Moreover, thiolatocobalamins are remarkably nontoxic in vitro at supraphysiological concentrations (>2 mM). Our results demonstrate that thiolatocobalamins act as powerful but benign antioxidants at pharmacological concentrations. Because inflammatory oxidative stress is a component of many conditions, including atherosclerosis, dementia, and trauma, their utility in treating such disorders merits further investigation.

Vitamin B12 and Redox Homeostasis: Cob(II)alamin Reacts with Superoxide at Rates Approaching Superoxide Dismutase (SOD)

We report a kinetic study of the reaction between superoxide and an important intracellular form of vitamin B(12), cob(II)alamin. Superoxide is implicated in the pathophysiology of many inflammatory diseases, whereas vitamin B(12) derivatives are often beneficial in their treatment. We found that cob(II)alamin reacts with superoxide at rates approaching those of superoxide dismutase itself, suggesting a probable mechanism by which vitamin B(12) protects against chronic inflammation and modulates redox homeostasis.

Alzheimer's disease and total plasma aminothiols

BACKGROUND Plasma homocysteine is elevated in Alzheimers disease, but little is known regarding levels of related aminothiols in the disease. We therefore determined total plasma homocysteine, cysteine, and glutathione levels in patients and control subjects and investigated their relationship with cognitive scores. METHODS We performed a prospective, case-controlled survey based in two UK Psychogeriatric Assessment Centres. Fifty patients with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer type were recruited together with 57 cognitively intact age- and gender-matched control subjects. Mini-Mental State and Alzheimers Disease Assessment Scale-Cognitive Subsection (ADAS-Cog) scores were determined for patients and control subjects. Aminothiols were assayed with an automated high-performance liquid chromatography (HPLC) system. RESULTS Patients had significantly elevated total plasma homocysteine (p <.001) and cysteine (p <.01), but there were no group differences for total plasma glutathione. Glutathione was, however, a highly significant and independent predictor of cognitive scores in patients (p =.002); lower plasma levels were associated with more severe cognitive impairment. CONCLUSIONS Total plasma homocysteine and cysteine are elevated in Alzheimers disease, suggesting intact transsulphuration but defective remethylation of homocysteine in the disease. Total plasma glutathione levels in patients correlate with cognitive scores. Taken together, these observations perhaps reflect the differential effects of Alzheimers disease-related oxidative stress on the two key pathways of homocysteine metabolism.

Transcobalamin polymorphism and serum holo-transcobalamin in relation to Alzheimer's disease

Isoforms of the vitamin B12 carrier protein transcobalamin (TC) might influence its cellular availability and contribute to the association between disrupted single-carbon metabolism and Alzheimer’s disease (AD). We therefore investigated the relationships between the TC 776C>G (Pro259Arg) genetic polymorphism, total serum cobalamin and holo-TC levels, and disease onset in 70 patients with clinically diagnosed AD and 74 healthy elderly controls. TC 776C>G polymorphism was also determined for 94 histopathologically confirmed AD patients and 107 controls. Serum holo-TC levels were significantly higher in TC 776C homozygotes (p = 0.04). Kaplan-Meier survival functions differed between homozygous genotypes (Cox’s F-Test F(42, 46) = 2.1; p = 0.008) and between 776C homozygotes and heterozygotes (Cox’s F test F(46, 108) = 1.7; p = 0.02). Proportionately fewer TC 776C homozygotes appear to develop AD at any given age, but this will require confirmation in a longitudinal study.

L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline.

Neuroinflammatory oxidative stress occurs early in AD pathology. Elevated blood Hcy is a useful marker for such neuroinflammation. Hcy contributes to pathological cascades involving AP and NFTs. In AD, Hcy should be lowered by B-vitamin supplements and NAC.

Analogues, Ageing and Aberrant Assimilation of Vitamin B12 in Alzheimer’s Disease

Vitamin B12 assimilation might be disrupted in patients with Alzheimer’s disease. We therefore measured B12 carrier protein saturation and inactive B12 ‘analogues’ in patients compared with healthy elderly individuals in a prospective case-controlled survey. Twenty-three patients, aged 60 or over, with features compatible with DSM-IV criteria for primary degenerative dementia of the Alzheimer type were recruited together with 18 cognitively intact age-matched control subjects. Total vitamin B12 (active corrinoids), holo- and apo-haptocorrin and transcobalamin were measured in serum. B12 analogues (inactive corrinoids) were estimated from the difference between R-binder-determined corrinoids and an intrinsic factor based B12 assay. Alzheimer patients had significantly lower active corrinoid than control subjects and the analogue/corrinoid ratio was significantly higher in the Alzheimer group. The inter-relationship between age, analogues and transcobalamin polarised patients into two distinct groups. Two disparate mechanisms might exist for the development of cerebral B12 deficiency in Alzheimer’s disease, although both imply a disruption of selective B12 assimilation and analogue elimination in such patients.

Synthesis, Synchrotron X-ray Diffraction, and Kinetic Studies on the Formation of a Novel Thiolatocobalamin of Captopril: Evidence for cis-trans Isomerization in the β-Axial Ligand

The orally administered therapeutic captopril is widely used for treating hypertension, congestive heart failure, and cardiovascular disease. However, a number of undesirable side effects are associated with high doses of captopril. By coordinating a therapeutic to the upper (= beta) axial site of the naturally occurring macrocycle cobalamin (vitamin B(12)), the absorption and cellular uptake of the therapeutic can be significantly enhanced. We report the synthesis of captopril-cobalamin, a derivative of vitamin B(12) in which captopril is bound via its thiol group at the beta-axial site of cobalamin. Characterization of captopril-cobalamin by (1)H NMR spectroscopy and X-ray diffraction shows that captopril-cobalamin exists in both solution and the solid state as a mixture of geometric isomers. Kinetic studies on the formation of captopril-cobalamin have been carried out, and the data fits a model in which the thiol form (RSH, k(1) = 40.9 +/- 1.2 M(-1) s(-1)) and the thiolate form of captopril (RS(-), k(2) = 660 +/- 170 M(-1) s(-1)) react rapidly with aquacobalamin.