Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

Atticus H. Hainsworth; Natalie E. Yeo; Erica M. Weekman; Donna M. Wilcock

doi:10.1016/j.bbadis.2015.11.015

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

Atticus H. Hainsworth
, Natalie E. Yeo
, Erica M. Weekman
, Donna M. Wilcock

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

Abstract

Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10 μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200 μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100 μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B₆, B₁₂ and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID).Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100 μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B₆, B₁₂ and folate); target the at-risk age range and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Original language	English
Pages (from-to)	1008-1017
Number of pages	10
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1862
Issue number	5
DOIs	https://doi.org/10.1016/j.bbadis.2015.11.015
State	Published - May 1 2016

Bibliographical note

Publisher Copyright:
© 2015 Elsevier B.V.

Funding

We are very grateful to AD Smith and H Refsum for their helpful comments on clinical trials. Funding of Dr. Hainsworth's laboratory comes from ADDF (grant no. 20140901 ), Alzheimers Society ( PG146/151 ) and Alzheimers Research UK ( PPG2014A-8 ). Funding for Dr. Wilcock's work on hyperhomocysteinemia comes from the National Institute of Neurological Disorders and Stroke/National Institutes of Health grant 1R01NS079637 .

Funders	Funder number
National Institutes of Health (NIH)	1R01NS079637
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
Alzheimer's Drug Discovery Foundation	20140901
Alzheimer's Society	PG146/151
Alzheimer’s Research United Kingdom	PPG2014A-8

Keywords

Brain
Dementia
Homocysteine
Hyperhomocysteinemia
Vascular cognitive impairment

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology

Access to Document

10.1016/j.bbadis.2015.11.015

Cite this

@article{0d46612b978e4f5195390f7ab22e916c,

title = "Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)",

abstract = "Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10 μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200 μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100 μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID).Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100 μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.",

keywords = "Brain, Dementia, Homocysteine, Hyperhomocysteinemia, Vascular cognitive impairment",

author = "Hainsworth, \{Atticus H.\} and Yeo, \{Natalie E.\} and Weekman, \{Erica M.\} and Wilcock, \{Donna M.\}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier B.V.",

year = "2016",

month = may,

day = "1",

doi = "10.1016/j.bbadis.2015.11.015",

language = "English",

volume = "1862",

pages = "1008--1017",

number = "5",

}

TY - JOUR

T1 - Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

AU - Hainsworth, Atticus H.

AU - Yeo, Natalie E.

AU - Weekman, Erica M.

AU - Wilcock, Donna M.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10 μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200 μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100 μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID).Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100 μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

AB - Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10 μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200 μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100 μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID).Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100 μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

KW - Brain

KW - Dementia

KW - Homocysteine

KW - Hyperhomocysteinemia

KW - Vascular cognitive impairment

UR - https://www.scopus.com/pages/publications/84950161678

UR - https://www.scopus.com/pages/publications/84950161678#tab=citedBy

U2 - 10.1016/j.bbadis.2015.11.015

DO - 10.1016/j.bbadis.2015.11.015

M3 - Article

AN - SCOPUS:84950161678

SN - 0925-4439

VL - 1862

SP - 1008

EP - 1017

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

IS - 5

ER -

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this