Homocysteine is associated with hippocampal and white matter atrophy in older subjects with mild hypertension

Firbank, Michael; Narayan, Shyam; Saxby, Brian K.; Ford, Gary A.; O’Brien, John T.

doi:10.1017/s1041610210000499

Cited by 45 publications

(32 citation statements)

References 25 publications

(53 reference statements)

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“…This new cortical mapping study complements prior studies associating high levels of homocysteine with overall brain volume reduction, WM atrophy rate, baseline volume and atrophy rate of the hippocampus and medial temporal lobe (Clarke et al, 1998a, den Heijer et al, 2003, Douaud et al, 2013, Firbank et al, 2010, Williams et al, 2002), lower tissue volumes in frontal and parietal WM (Rajagopalan et al, 2011), greater cortical atrophy (den Heijer et al, 2003), longitudinal ventricular volume enlargement in elderly individuals with arteriosclerotic disease (Jochemsen et al, 2012), lower whole brain GM volume in non-demented elderly (Whalley et al, 2003) in humans and with lower GM volume and density in prefrontal cortices and striatum in rhesus monkeys (Willette et al, 2012). Our prior study in an almost entirely overlapping subject population – but with a different method, TBM – found WM tissue contraction (Rajagopalan et al, 2011) in areas that structurally connect the GM regions we see here in the cortex.…”

Section: Discussionsupporting

confidence: 64%

Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative

Madsen

Rajagopalan

Joshi

et al. 2015

Neurobiology of Aging

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A significant portion of our risk for dementia in old age is associated with lifestyle factors (diet, exercise, and cardiovascular health) that are modifiable, at least in principle. One such risk factor – high homocysteine levels in the blood – is known to increase risk for Alzheimer’s disease and vascular disorders. Here we set out to understand how homocysteine levels relate to 3D surface-based maps of cortical gray matter distribution (thickness, volume, surface area) computed from brain MRI in 803 elderly subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals with higher plasma levels of homocysteine had lower gray matter thickness in bilateral frontal, parietal, occipital and right temporal regions; and lower gray matter volumes in left frontal, parietal, temporal, and occipital regions, after controlling for diagnosis, age, and sex, and after correcting for multiple comparisons. No significant within-group associations were found in cognitively healthy people, mild cognitive impairment, or Alzheimer’s disease. These regional differences in gray matter structure may be useful biomarkers to assess the effectiveness of interventions, such as vitamin B supplements, that aim to prevent homocysteine-related brain atrophy by normalizing homocysteine levels.

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Section: Discussionsupporting

confidence: 64%

Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative

Madsen

Rajagopalan

Joshi

et al. 2015

Neurobiology of Aging

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“…HHCy is associated with an increased rate of hippocampal atrophy [16] and with accelerated cognitive decline in AD patients [88] and is now accepted as a risk factor for AD [6]. Plasma HCy concentration is strongly associated with hippocampal atrophy, white matter lesions and lacunar infarcts in cross-sectional studies [32,61,117,123]. The association with hippocampal atrophy appears to be independent of amyloid pathology [14].…”

Section: Introductionmentioning

confidence: 99%

“…Multiple studies have shown that mild-moderate HHCy is a risk factor for SVD [32,44,45,61,61,62,117,123]. In case-control studies HHCy was positively-associated with SVD severity, with highest plasma total HCy concentration (plasma [HCy]; average 20 µM) in patients with confluent leukoaraiosis on MRI scans, indicative of more severe SVD [44,61].…”

Section: Introductionmentioning

confidence: 99%

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

Hainsworth

Yeo

Weekman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3–10µM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100–200µM), mild-moderate hyperhomocysteinemia ([HCy]: 10–100µM) 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 trails of combined B-vitamin supplementation are called for, incorporating lessons from previous trails 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; target cohorts with low baseline B-vitamin status.

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“…Further studies are required to determine the mechanisms that might be responsible for homocysteine-related atrophy. In a separate paper we address the relationship between homocysteine concentrations on grey and white matter atrophy [23]. Our data strongly support the conduct of interventional studies to investigate the efficacy of homocysteine-lowering treatment (e.g.…”

Section: Discussionmentioning

confidence: 54%

Elevated Plasma Homocysteine Is Associated with Increased Brain Atrophy Rates in Older Subjects with Mild Hypertension

Narayan¹,

Firbank²,

Saxby³

et al. 2011

Dement Geriatr Cogn Disord

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We determined using serial MR imaging whether raised plasma homocysteine levels are associated with increased brain atrophy, white matter lesion (WML) progression or incidence of silent brain infarcts (SBIs) in older hypertensive subjects. Brain atrophy rates (0.58 ± 0.48% per year, mean ± SD) were significantly correlated with homocysteine (β = 0.46, p = 0.001 homocysteine; β = 0.44, p = 0.007 homocysteine/folate/B12 models) but not with folate or B12 levels. Progression of WML (0.08 ± 0.16%) was not associated with homocysteine level (B = 0.01, p = 0.29). New SBIs were uncommon. In older hypertensive individuals, plasma homocysteine levels are associated with increased rates of whole-brain atrophy but not WML progression.

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Homocysteine is associated with hippocampal and white matter atrophy in older subjects with mild hypertension

Abstract: In older hypertensives, plasma homocysteine levels are associated with increased rates of progressive white matter and hippocampal atrophy.

Cited by 45 publications

References 25 publications

Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative

Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative

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

Elevated Plasma Homocysteine Is Associated with Increased Brain Atrophy Rates in Older Subjects with Mild Hypertension

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