Plasma antioxidants and risk of dementia in older adults

Manja Koch, Jeremy D Furtado, Héléne Toinét Cronjé, Steven T DeKosky, Annette L Fitzpatrick, Oscar L Lopez, Lewis H Kuller, Kenneth J Mukamal, Majken K Jensen

Alzheimers Dement (N Y) . 2021 Sep 5;7(1):e12208. doi: 10.1002/trc2.12208. eCollection 2021.

Abstract

Introduction: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.

Methods: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer’s disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-β-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD.

Results: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β-carotene, or vitamin E supplements. Higher trans-β-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-β-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29).

Discussion: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

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The effect of α-tocopherol, α- and γ-tocotrienols on amyloid-β aggregation and disaggregation in vitro

Nor Faeizah Ibrahim, Hamizah Shahirah Hamezah, Daijiro Yanagisawa, Mayumi Tsuji, Yuji Kiuchi, Kenjiro Ono, Ikuo Tooyama

Biochem Biophys Rep . 2021 Sep 10;28:101131. doi: 10.1016/j.bbrep.2021.101131. eCollection 2021 Dec.

Abstract

One of the neuropathological hallmarks of Alzheimer’s disease (AD)-causing neurodegeneration and consequent memory deterioration, and eventually, cognitive decline-is amyloid-β (Aβ) aggregation forming amyloid plaques. Our previous study showed the potential of a tocotrienol-rich fraction-a mixture of naturally occurring of vitamin E analogs-to inhibit Aβ aggregation and restore cognitive function in an AD mouse model. The current study examined the effect of three vitamin E analogs-α-tocopherol (α-TOC), α-tocotrienol (α-T3), and γ-tocotrienol (γ-T3)-on Aβ aggregation, disaggregation, and oligomerization in vitro. Thioflavin T (ThT) assay showed α-T3 reduced Aβ aggregation at 10 μM concentration. Furthermore, both α-T3 and γ-T3 demonstrated Aβ disaggregation, as shown by the reduction of ThT fluorescence. However, α-TOC showed no significant effect. We confirmed the results for ThT assays with scanning electron microscopy imaging. Further investigation in photo-induced cross-linking of unmodified protein assay indicated a reduction in Aβ oligomerization by γ-T3. The present study thus revealed the individual effect of each tocotrienol analog in reducing Aβ aggregation and oligomerization as well as disaggregating preformed fibrils.

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Dietary intake of tocopherols and risk of incident disabling dementia

Shoko Aoki, Kazumasa Yamagishi, Koutatsu Maruyama, Rie Kishida, Ai Ikeda, Mitsumasa Umesawa, Cui Renzhe, Yasuhiko Kubota, Mina Hayama-Terada, Yuji Shimizu, Isao Muraki, Hironori Imano, Tomoko Sankai, Takeo Okada, Akihiko Kitamura, Masahiko Kiyama, Hiroyasu Iso

Sci Rep . 2021 Aug 12;11(1):16429. doi: 10.1038/s41598-021-95671-7.

Abstract

Tocopherols, strong antioxidants, may be useful in preventing dementia, but the epidemiological evidence is insufficient. We performed a community-based follow-up study of Japanese, the Circulatory Risk in Community Study, involving 3739 people aged 40-64 years at baseline (1985-1999). Incident disabling dementia was followed up from 1999 through 2020. For subtype analysis, we classified disabling dementia into that with and that without a history of stroke. Dietary intake of tocopherols (total, α, β, γ, and δ) were estimated using 24-h recall surveys. During a median follow-up of 19.7 years, 670 cases of disabling dementia developed. Total tocopherol intake was inversely associated with risk of disabling dementia with multivariable hazard ratios (95% confidence intervals) of 0.79 (0.63-1.00) for the highest versus lowest quartiles of total tocopherol intake (P for trend = 0.05). However, the association was strengthened when further adjusted for α-linolenic acid intake (Spearman correlation with total tocopherol intake = 0.93), with multivariable hazard ratios of 0.50 (0.34-0.74) (P for trend = 0.001) but was weakened and nonsignificant when further adjusted for linoleic acid intake (Spearman correlation with total tocopherol intake = 0.92), with multivariable hazard ratios of 0.69 (0.47-1.01) (P for trend = 0.05). Similar but nonsignificant inverse associations were observed for α-, γ-, and δ-tocopherols but not for β-tocopherol. These results were similar regardless of the presence of a history of stroke. Dietary tocopherol intake was inversely associated with risk of disabling dementia, but its independent effect was uncertain owing to a high intercorrelation of α-linolenic linoleic acids with total tocopherol intake. Even with such confounding, a diet high in tocopherols may help prevent the onset of dementia.

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Effects of Co-administration of Vitamin E and Lithium Chloride on Chronic Constriction Injury-induced Neuropathy in Male Wistar Rats: Focus on antioxidant and anti-inflammatory mechanisms

Kingsley Dominic Esu, Ahmed Olalekan Bakare, Bamidele Victor Owoyele

Pain Pract . 2021 Aug 5. doi: 10.1111/papr.13064. Online ahead of print.

Abstract

Objectives: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit. E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit. E which may be complementary to the antinociceptive effects of the two substances.

Methods: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight (b.w) were randomly assigned to six experimental groups and administered with either normal saline, Vit. E, LiCl, or their combination, once daily for twenty-one (21) days. CCI was used to induce NP and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behaviour. Biochemical parameters were assessed in the dorsal root ganglion (DRG) after twenty-one days of treatment.

Results: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit.E. synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit.E. or LiCl. Combined doses of Vit.E. and LiCl significantly increases the explorative behaviour in the OFM. CCI increased malondialdehyde (MDA), tumour necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide (CGRP), calcium ion (Ca2+ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit.E. significantly reduced MDA, TNF-α, but increased SOD compared with ligated control.

Discussion: The findings revealed that the synergistic effects of the co-administration of Vit. E and LiCl in ameliorating neuropathic pain are mediated by their anti-inflammatory and antioxidant properties.

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Increased α-tocopherol metabolism in horses with equine neuroaxonal dystrophy

Erin N Hales, Hadi Habib, Gianna Favro, Scott Katzman, R Russell Sakai, Sabin Marquardt, Matthew H Bordbari, Brittni Ming-Whitfield, Janel Peterson, Anna R Dahlgren, Victor Rivas, Carolina Alanis Ramirez, Sichong Peng, Callum G Donnelly, Bobbi-Sue Dizmang, Angelica Kallenberg, Robert Grahn, Andrew D Miller, Kevin Woolard, Benjamin Moeller, Birgit Puschner, Carrie J Finno

J Vet Intern Med . 2021 Jul 31. doi: 10.1111/jvim.16233. Online ahead of print.

Abstract

Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with a vitamin E deficiency within the first year of life. Vitamin E consists of 8 isoforms metabolized by the CYP4F2 enzyme. No antemortem diagnostic test currently exists for eNAD/EDM.

Hypothesis/objectives: Based on the association of α-tocopherol deficiency with the development of eNAD/EDM, we hypothesized that the rate of α-tocopherol, but not γ-tocopherol or tocotrienol metabolism, would be increased in eNAD/EDM-affected horses.

Animals: Vitamin E metabolism: Proof of concept (POC) study; eNAD/EDM-affected (n = 5) and control (n = 6) horses. Validation study: eNAD/EDM-affected Quarter Horses (QHs; n = 6), cervical vertebral compressive myelopathy affected (n = 6) horses and control (n = 29) horses. CYP4F2 expression and copy number: eNAD/EDM-affected (n = 12) and age- and sex-matched control (n = 11-12) horses.

Methods: The rates of α-tocopherol/tocotrienol and γ-tocopherol/tocotrienol metabolism were assessed in equine serum (POC and validation) and urine (POC only) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative reverse-transcriptase PCR (qRT-PCR) and droplet digital (dd)-PCR were used to assay expression and genomic copy number of a CYP4F2 equine ortholog.

Results: Metabolic rate of α-tocopherol was increased in eNAD/EDM horses (POC,P < .0001; validation, P = .03), with no difference in the metabolic rate of γ-tocopherol. Horses with eNAD/EDM had increased expression of the CYP4F2 equine orthologue (P = .02) but no differences in copy number.

Conclusions and clinical importance: Increased α-tocopherol metabolism in eNAD/EDM-affected QHs provides novel insight into alterations in vitamin E processing in eNAD/EDM and highlights the need for high-dose supplementation to prevent the clinical phenotype in genetically susceptible horses.

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Effects of vitamin E on neurodegenerative diseases: an update

Mehmet Arif Icer, Neslihan Arslan, Makbule Gezmen-Karadag

Acta Neurobiol Exp (Wars) . 2021;81(1):21-33. doi: 10.21307/ane-2021-003.

Abstract

Vitamin E deficiency is associated with many neurological problems. Although the mechanisms of vitamin E action in neurodegenerative diseases are not clear, there are many possible mechanisms. Examples of such mechanisms are the protective effects of vitamin E against oxidative stress damage and its suppressive role in the expression of many genes involved in the development of neurodegeneration. Many studies have evaluated the relationship between vitamin E intake or vitamin E levels in body fluids and neurodegenerative diseases. Some studies concluded that vitamin E can play a protective role in neurodegeneration with respect to diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and amyotrophic lateral sclerosis (ALS). Vitamin E supplementation was also associated with risk factors for some neurodegenerative diseases. In this review, we discuss the possible effects of vitamin E on the development and course of AD, PD, stroke and ALS, and the potential mechanisms involved.

Vitamin E deficiency is associated with many neurological problems. Although the mechanisms of vitamin E action in neurodegenerative diseases are not clear, there are many possible mechanisms. Examples of such mechanisms are the protective effects of vitamin E against oxidative stress damage and its suppressive role in the expression of many genes involved in the development of neurodegeneration. Many studies have evaluated the relationship between vitamin E intake or vitamin E levels in body fluids and neurodegenerative diseases. Some studies concluded that vitamin E can play a protective role in neurodegeneration with respect to diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and amyotrophic lateral sclerosis (ALS). Vitamin E supplementation was also associated with risk factors for some neurodegenerative diseases. In this review, we discuss the possible effects of vitamin E on the development and course of AD, PD, stroke and ALS, and the potential mechanisms involved.

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Associations between vitamin E, oxidative stress markers, total homocysteine levels, and physical activity or cognitive capacity in older adults

Ahmad H Alghadir, Sami A Gabr, Shahnawaz Anwer, Heng Li

Sci Rep . 2021 Jun 18;11(1):12867. doi: 10.1038/s41598-021-92076-4.

Abstract

This study examined the associations between vitamin E, oxidative stress markers, total homocysteine levels, and physical activity or cognitive capacity in older adults. One hundred and six older adults (62 men, 44 women) within the age range of 56-81 years participated. The Global Physical Activity Questionnaire and the Loewenstein Occupational Therapy Cognitive Assessment were used to assess physical activity and cognitive function, respectively. Vitamin E (e.g., α-tocopherol and γ-tocopherol), oxidative stress markers (e.g., total antioxidant capacity and nitric oxide), and total homocysteine were estimated. There were significant associations between physical activity (high versus moderate versus poor) and all biomarkers (all p = 0.000, and p = 0.010 for γ-tocopherol). While total homocysteine and total antioxidant capacity were significantly associated with cognitive capacity (p = 0.000), vitamin E levels (e.g., α-tocopherol and γ-tocopherol) and nitric oxide (p = 0.354, 0.103 and 0.060, respectively) were not related to cognitive capacity in older adults. This study concludes that physical activity was associated with Vitamin E, oxidative stress markers, total homocysteine, and cognitive capacity in older adults. Although cognitive capacity was associated with total homocysteine and total antioxidant capacity, it was unrelated to vitamin E levels and nitric oxide in older adults.

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Protective Effects of Vitamin E on Chemotherapy-Induced Peripheral Neuropathy: A Meta-Analysis of Randomized Controlled Trials

Huikai Miao, Rongzhen Li, Dongni Chen, Jia Hu, Youfang Chen, Chunmei Xu, Zhesheng Wen

Ann Nutr Metab . 2021 Jun 18;1-11. doi: 10.1159/000515620. Online ahead of print.

Abstract

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common symptom, but prophylactic measures cannot still be carried out effectively. In addition, the efficacy of vitamin E in preventing peripheral neurotoxicity caused by chemotherapy is inconclusive. Therefore, we collected the relevant randomized controlled trials (RCTs) and performed a meta-analysis to examine whether the vitamin E has a positive effect in CIPN.

Methods: We searched PubMed, EMBASE, Cochrane, and other databases in December 2019 for eligible trials. Two reviewers conducted the analysis independently when studies were homogeneous enough.

Results: Eight RCTs, involving 488 patients, were identified. Upon pooling these RCTs, patients who received vitamin E supplementation of 600 mg/day had a lower incidence of CIPN (risk ratio [RR] 0.31; 95% confidence interval [CI] 0.14-0.65; p = 0.002) than the placebo group. Vitamin E played a key role in decreasing the incidence of peripheral neuropathy in the cisplatin chemotherapy group (RR 0.28; 95% CI 0.14-0.54; p = 0.0001). Moreover, vitamin E supplementation significantly decreased patients’ sural amplitude after 3 rounds of chemotherapy (RR -2.66; 95% CI -5.09 to -0.24; p = 0.03) in contrast with that of placebo supplementation, while no significant difference was observed when patients were treated with vitamin E after 6 rounds of chemotherapy. In addition, the vitamin E-supplemented group had better improvement in the neurotoxicity score and lower incidence of reflexes and distal paraesthesias than the control group.

Conclusion: Available data in this meta-analysis showed that vitamin E supplementation can confer modest improvement in the prevention of CIPN.

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Effect of dietary vitamins C and E on the risk of Parkinson’s disease: A meta-analysis

Min Cheol Chang, Sang Gyu Kwak, Soyoung Kwak

Clin Nutr . 2021 May 21;40(6):3922-3930. doi: 10.1016/j.clnu.2021.05.011. Online ahead of print.

Abstract

Background & aims: A neuroprotective effect of dietary vitamins C and E on Parkinson’s disease (PD) has been suggested, however, several human studies have reported controversial results. Therefore, we conducted a meta-analysis on the effect of vitamins C and E on the risk of Parkinson’s disease.

Methods: A comprehensive literature search was conducted using the PubMed, EMBASE, Cochrane Library, and SCOPUS databases for studies published up to January 23, 2021. We included studies that reported (1) intake of vitamins C and E using validated methods; (2) assessment of odds ratio (OR), relative risk (RR), or hazard ratio (HR); and (3) patients with PD identified by a neurologist, hospital records, or death certificates. The Comprehensive Meta-Analysis Software 2 program was used for statistical analyses of the pooled data.

Results: A total of 12 studies (four prospective cohort and eight case-control studies) were included in our meta-analysis. No significant risk reduction was observed in the high vitamin C intake group compared to low intake group. On the other hand, the high vitamin E intake group showed a significantly lower risk of development of PD than the low intake group (pooled OR = 0.799. 95% CI = 0.721 to 0.885).

Conclusions: We conclude that vitamin E might have a protective effect against PD, while vitamin C does not seem to have such an effect. However, the exact mechanism of the transport and regulation of vitamin E in the CNS remains elusive, and further studies would be necessary in this field.

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Vitamin E for the Prevention of Chemotherapy-Induced Peripheral Neuropathy: A meta-Analysis

Jie Chen, Haili Shan, Wenjun Yang, Jiali Zhang, Haibin Dai, Ziqi Ye

Front Pharmacol . 2021 May 13;12:684550. doi: 10.3389/fphar.2021.684550. eCollection 2021.

Abstract

Background: Vitamin E has been increasingly used to prevent chemotherapy-induced peripheral neuropathy (CIPN) in recent years. However, it is still unclear whether vitamin E can effectively prevent CIPN. Methods: We searched all clinical studies in the Embase, Cochrane Library, Clinicaltrials.gov, and PubMed databases from inception to December 2020. We performed a meta-analysis of 9 randomized controlled trials (RCTs) with 486 patients that compared the vitamin E group with the control group. Outcomes of the study were incidence of all-grade CIPN, incidence of severe CIPN, and the total neuropathy scores (TNS). Random effect models were used to make the meta-analysis results more cautious. Results: Notably, vitamin E significantly reduced the incidence of all-grade CIPN (overall risk ratio (RR) = 0.55, 95% CI: 0.36, 0.85, I2 = 77.3%, p = 0.007), and TNS (overall standard mean difference (SMD) = -0.64, 95% CI: 1.03, -0.25, I2 = 42.7%, p = 0.001). However, the results of the subgroup analysis, which included only double-blind RCTs, suggested that vitamin E did not significantly reduce the incidence of all-grade CIPN (overall RR = 0.52, 95% CI: 0.07, 4.06, I2 = 77.5%, p = 0.531). Moreover, there was no significant difference in the incidence of severe CIPN between these two arms (p = 0.440). Conclusion: The results of our meta-analysis suggests that vitamin E has a beneficial effect on the incidence and symptoms of CIPN. However, routine prophylactic use of vitamin E is still not recommended. Moreover, more high-quality double-blind RCTs are needed to further validate the effects of vitamin E in prevention of CIPN.

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