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Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking.
Sonnen, JA, Larson, EB, Gray, SL, Wilson, A, Kohama, SG, Crane, PK, Breitner, JC, Montine, TJ
Annals of neurology. 2009;65(2):226-9
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Plain language summary
Previous evidence supports a pathogenic role for increased free radical damage to brain regions in Alzheimer’s disease (AD). Adult Changes in Thought (ACT), a longitudinal study assessing brain aging and incident dementia among 3392 adults, has found that consumption of vitamin E, vitamin C or both was not associated with reduced risk of developing dementia over 5.5 years of follow up. The aim of this study was to determine whether this lack of therapeutic effect is associated with a measureable pharmacologic effect. This autopsy study examined 71 brains from ACT and found that increased free radical damage was associated with AD, microvascular brain injury and smoking, but not with antioxidant supplement usage. Based on the lack of therapeutic effect from the ACT and no apparent pharmacologic effect from this autopsy study, the authors conclude that future clinical trials for AD should consider dietary sources rather than supplements and investigate other antioxidants and various combinations.
Abstract
Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study.
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Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum disease.
Wierzbicki, AS, Mayne, PD, Lloyd, MD, Burston, D, Mei, G, Sidey, MC, Feher, MD, Gibberd, FB
Journal of lipid research. 2003;44(8):1481-8
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Phytanic acid (PA) is a branched-chain fatty acid, found in many animal products, that, unlike most fatty acids, cannot be metabolised by beta-oxidation. Instead, it undergoes alpha-oxidation in the peroxisome. Adult Refsum Disease is a genetic neurological disease, in which alpha-oxidation is impaired, resulting in the accumulation of PA in nerves and fat tissues. Other pathways for the metabolism of PA are not fully understood, such as omega-oxidation, which results in the production of 3-methyl-organic acids (3-MAA). This study assessed the contribution of the omega-oxidation pathway to the metabolism of PA by measuring 3-MAA excretion in patients with ARD. Eleven patients with ARD were put on a low-PA diet for 12 weeks. Blood, urine and tissue samples were taken at the start and end of the 12-week period to assess levels of PA and its metabolites. The low-PA diet led to an average 21% fall in blood PA levels over 12 weeks. The capacity of the omega-oxidation pathway was 6.9mg PA/day. The authors concluded that the omega-oxidation pathway can metabolise PA ingested by patients with ARD. Therefore, omega-oxidation is a potential target for therapeutic intervention to reduce PA levels in ARD patients.
Abstract
Adult Refsum disease (ARD) is associated with defective alpha-oxidation of phytanic acid (PA). omega-Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, omega-oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the omega-oxidation pathway was 6.9 (2.8-19.4) mg [20.4 (8.3-57.4) micromol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. omega-Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 +/- 58% in parallel with the 158 (125-603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The omega-oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration. omega-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.