CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer’s Disease and Cerebrovascular Disease

Shankle, William R.; Hara, Junko; Barrentine, Lori W.; Curole, Melanie

doi:10.3233/jad-160241

Cited by 24 publications

(11 citation statements)

References 43 publications

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“…The longitudinal improvement in processing speed and attention (Digit Symbol Coding) among those who received high-dose B-vitamin therapy is similar to the improvement in processing speed and memory in the treatment arm of the FACIT trial (18). Such an effect would be consistent with the prevention of cortical damage by B-vitamin therapy as observed in the VITACOG trial (20), and in a similar recent intervention (51, 52), and which is associated with decline in executive function as recently described by Zhang (53). Our findings suggest that these aspects of cognitive impairment might be partially reversible among kidney transplant recipients, and that at least attention and processing speed be amenable to further improvement through vitamin therapy.…”

Section: Discussionsupporting

confidence: 83%

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

Scott¹,

Rogers²,

Weiner³

et al. 2017

J Prev Alz Dis

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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.

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Section: Discussionsupporting

confidence: 83%

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

Scott¹,

Rogers²,

Weiner³

et al. 2017

J Prev Alz Dis

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“…Abnormally high levels of homocysteine have been reported to be a significant risk factor for the development of a wide range of diseases such as in cerebrovascular diseases [ 241 , 242 , 243 , 244 ], various CVDs [ 245 , 246 , 247 , 248 , 249 ], cognitive impairment including Alzheimer’s disease [ 250 , 251 , 252 ], fractures [ 253 , 254 , 255 ], and mortality [ 256 ]. Deficiencies of vitamin B12, folate, or vitamin B6 seem to play an important role in the occurrence of hyperhomocysteinemia, because they are essential for homocysteine metabolism ( Figure 2 ), and treatment with B-vitamin supplementation (B6, B12, and folate) has been demonstrated to effectively lower homocysteine levels [ 257 , 258 , 259 , 260 , 261 ]. The majority of these trials have focused on the prevention of pathological changes associated with vascular dysfunction, because folic acid prevents homocysteine-induced proinflammatory status and apoptosis of endothelial cells [ 248 , 262 ].…”

Section: Nutrients and Their Metabolites And Enzymes Related To Dnmentioning

confidence: 99%

“…A high level of homocysteine in the blood seems to provoke endothelial cell injury; this leads to inflammation in the blood vessels and accelerates atherogenesis, which can result in ischemic injury. Several studies of homocysteine-lowering treatments have shown a favorable effect on vascular pathologies associated with hyperhomocysteinemia [ 257 , 263 , 264 ]. However, other studies and meta-analyses have demonstrated that lowering homocysteine using B vitamins had no significant effect on stroke prevention [ 260 , 261 , 265 , 266 ], prevention of myocardial infarction [ 260 , 261 , 266 , 267 , 268 , 269 , 270 ], individual or global cognitive function [ 271 , 272 , 273 ], or other pathological conditions [ 274 , 275 , 276 ].…”

Section: Nutrients and Their Metabolites And Enzymes Related To Dnmentioning

confidence: 99%

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

Soda

2018

IJMS

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Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

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“…These B vitamins are necessary to convert homocysteine to methionine/cysteine, thus, preventing homocysteine-stimulated ROS production. Methylated forms have been found to delay cortical and white matter atrophy, yet further study is needed to determine the optimal form, dose and patient population in the preventative spectrum (e.g., based on nutrigenomics such as MTHFR mutations) for which B-vitamin supplementation is best suited ( Shankle et al, 2016 ).…”

Section: Interventions For Alzheimer’s Disease Risk Reductionmentioning

confidence: 99%

Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention

Schelke

Attia²,

Palenchar³

et al. 2018

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease-modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms—dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity—involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases.

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CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer’s Disease and Cerebrovascular Disease

Cited by 24 publications

References 43 publications

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

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

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention

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