Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia.

Brittani R Price,Donna M Wilcock,Erica M Weekman

doi:10.3389/fnagi.2018.00350

Abstract

Behind only Alzheimer’s disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10–40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, preclinical and clinical data shows it is not. Clinical trials using B vitamin supplementation have shown conflicting results about the benefits of lowering homocysteine and issues have arisen over proper study design within the trials. Studies using cell culture and animal models have proposed several mechanisms for homocysteine-induced cognitive decline, providing other targets for therapeutics. For this review, we will focus on HHcy as a risk factor for VCID, specifically, the different mechanisms proposed for homocysteine-induced cognitive decline and the clinical trials aimed at lowering plasma homocysteine.

Highlights

Vascular contributions to cognitive impairment and dementia (VCID) are defined as the conditions arising from vascular brain injuries that induce significant changes to memory, thinking, and behavior
Studies have shown that serum homocysteine levels are inversely related to cognitive function in patients with dementia and elevated levels are more common among vascular contributions to cognitive impairment and dementia (VCID) patients than among Alzheimer’s disease (AD) patients (Miller et al, 2002; Clarke et al, 2003)
800 μg folic acid, perceptual speed, (PLM) test vitamin observed in participants

Summary

INTRODUCTION

Vascular contributions to cognitive impairment and dementia (VCID) are defined as the conditions arising from vascular brain injuries that induce significant changes to memory, thinking, and behavior. Without homocysteine conversion to cysteine, either due to CBS mutations or a diet lacking in vitamin B6, glutathione levels decrease, leading to increased reactive oxygen species and oxidative stress. As suggested by the variety of cellular actions of homocysteine described above, there is no shortage of candidate mechanisms by which HHcy induces cognitive impairment despite known etiologies Both genetic mutations and dietary vitamin deficiencies can affect homocysteine levels resulting in HHcy. Several polymorphisms (notably C677T and A1298C) have been identified in the MTHFR gene in humans, which can induce severe HHcy (>100 μmol/L, termed homocystinuria) by limiting conversion of homocysteine back to methionine (Moll and Varga, 2015; Hainsworth et al, 2016). Duration of the intervention must be considered given that elderly individuals exhibiting

Study Limitations

Findings

CONCLUSION