Associations Between Elevated Homocysteine, Cognitive Impairment, and Reduced White Matter Volume in Healthy Old Adults

doi:10.1016/j.jagp.2012.10.017

The American Journal of Geriatric Psychiatry

Volume 21, Issue 2, February 2013, Pages 164-172

https://doi.org/10.1016/j.jagp.2012.10.017 Get rights and content

Objectives

Elevated homocysteine has emerged as a risk factor for cognitive impairment even in healthy elderly persons. Reduced brain volume and white matter hyperintensities also occur in healthy elderly as well, but the interrelationships between these have not been well studied. We report these interrelationships in non demented, relatively healthy, community-dwelling older adults from a single East Asian population.

Methods

Two hundred twenty-eight right-handed participants age 55 years and above were evaluated. Persons with medical conditions or neurological diseases other than well-controlled diabetes mellitus and hypertension were excluded. Participants underwent quantitative magnetic resonance imaging of the brain using a standardized protocol and neuropsychological evaluation. Plasma homocysteine, folate, vitamin B₁₂, and markers for cardiovascular risk: blood pressure, body mass index, fasting blood glucose, and lipid profile were measured.

Results

Elevated homocysteine was associated with reduced global cerebral volume, larger ventricles, reduced cerebral white matter volume, and lower cognitive performance in several domains. Elevated homocysteine was associated with reduced white matter volume (β = −20.80, t = −2.9, df = 223, p = 0.004) and lower speed of processing (β = −0.38, t = −2.1, df = 223, p = 0.03), even after controlling for age, gender, and education. However, the association between homocysteine and lower speed of processing disappeared after controlling for white matter volume. Elevated homocysteine was not associated with white matter hyperintensity volume or with hippocampal volume. Although homocysteine and folate levels were correlated, their effects on white matter volume were dissociated.

Conclusion

In non demented, relatively healthy adults, elevated homocysteine is associated with lower cognitive scores and reduced cerebral white matter volume. These effects can be dissociated from those related to white matter hyperintensities or reduced folate level.

Section snippets

Participants

A total of 240 healthy, community-based volunteers who were part of the Singapore-Longitudinal Aging Brain Study participated in the study.¹⁵ Participants were right-handed, of Han Chinese ethnicity, and age 55 years and above, with no known active medical condition other than uncomplicated and treated diabetes mellitus or hypertension.

Participants were excluded if they had any of the following: i) history of significant vascular events (i.e., myocardial infarction, stroke, or peripheral

Results

The mean age of the study participants was 65.4 years (SD: 6.2 years), and a slightly greater proportion were women (53.9%) (Table 1). The average number of years of education was 10.7 (SD: 3.4 years). There were relatively few current smokers (3.1%) and few regular alcohol drinkers (11.9%). We took an all-inclusive approach to reporting hypertension and diabetes, counting any individual who either self-reported these conditions or had any history of having been administered medication for

Discussion

This ethnically homogenous cohort of relatively healthy elderly persons enabled us to highlight the interrelationships between elevated homocysteine, brain structure, and cognitive performance.

References (46)

G. Ravaglia et al.
Homocysteine and folate as risk factors for dementia and Alzheimer disease
Am J Clin Nutr
(2005)
L. Feng et al.
Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study
Am J Clin Nutr
(2006)
M.F. Elias et al.
Homocysteine and cognitive performance: modification by the ApoE genotype
Neurosci Lett
(2008)
K.L. Tucker et al.
High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study
Am J Clin Nutr
(2005)
M.W. Chee et al.
Cognitive function and brain structure correlations in healthy elderly East Asians
Neuroimage
(2009)
M.F. Folstein et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975)
J. Jovicich et al.
Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data
Neuroimage
(2006)
D.H. Mathalon et al.
Correction for head size in brain-imaging measurements
Psychiatry Res
(1993)
V. Ganji et al.
Demographic, health, lifestyle, and blood vitamin determinants of serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey, 1988-1994
Am J Clin Nutr
(2003)
J. Lindenbaum et al.
Prevalence of cobalamin deficiency in the Framingham elderly population
Am J Clin Nutr
(1994)

C.-E. Zhang et al.

Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gammasecretase and phosphorylation of amyloid precursor protein in rat brain

Am J Pathol

(2009)

J. Durga et al.

Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial

Lancet

(2007)

S. Seshadri et al.

Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

N Engl J Med

(2002)

E. Nurk et al.

Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study

Ann Neurol

(2005)

C. Dufouil et al.

Homocysteine, white matter hyperintensities, and cognition in healthy elderly people

Ann Neurol

(2003)

S. Seshadri et al.

Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study

Arch Neurol

(2008)

T. den Heijer et al.

Homocysteine and brain atrophy on MRI of non-demented elderly

Brain

(2003)

S.E. Vermeer et al.

Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam Scan Study

Ann Neurol

(2002)

P. Sachdev et al.

Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men

Arch Neurol

(2004)

C.B. Wright et al.

Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study

Stroke

(2005)

A. Vogiatzoglou et al.

Vitamin B₁₂ status and rate of brain volume loss in community-dwelling elderly

Neurology

(2008)

W.T. Longstreth et al.

Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study

Arch Neurol

(2004)

J.I. Sheikh et al.

Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. Clinical Gerontology: A Guide to Assessment and Intervention

(1986)

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Together, these findings suggest 2 pathways through which Hcy impacts processing speed performance: a process leading to morphological differences in SGM driven by Hcy and an additional process related to WMH lesion load, which may exacerbate Hcy-related impacts on subcortical brain structures. Consistent with our findings, previous studies have linked high plasma concentrations of Hcy to cognitive dysfunction with an inverse association most noticeable for processing speed (Feng et al., 2013; Prins et al., 2002). Vascular white matter lesions have also been shown to affect structural cortical brain alterations, particularly in the frontal lobes (Habes et al., 2016), leading to the disruption of frontal-subcortical circuits by subcortical ischemic lesions (Righart et al., 2013).
Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50–89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.
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According to a study of healthy people from Chicago, the effect of HCY on cognitive performance may be mediated by enhanced white matter hyperintensity [32]. A study that included 228 older healthy individuals showed that white matter volume significantly mediated HCY-related processing speed deficits [9]. Those results are inconsistent with the findings of two earlier studies [8,28].
The mechanism by which high homocysteine (HCY) may aggravate cognitive impairment in patients with schizophrenia is not well understood. We aimed to test the hypothesis that hyperhomocysteinaemia may exacerbate cognitive deficits by mediating the decrease in cortical thickness in patients with schizophrenia. One hundred and sixty-seven first-episode patients with schizophrenia (FEPS) and 120 healthy controls (HCs) were included. Psychopathology and cognitive function were assessed using the Positive and Negative Symptom Scale and Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), respectively. Brain cortical thickness was measured by 3.0 T high-resolution magnetic resonance imaging. Serum HCY levels were tested using a sandwich enzyme-linked immunosorbent assay. Our findings showed that HCY levels in the FEPS were significantly higher than those in the HCs (P < 0.001). The MCCB total and subtest scores in the patients were significantly lower than those in the HCs (P < 0.001). The HCs had significantly higher cortical thickness than the patients (P < 0.001). Serum HCY levels were negatively correlated with Working Memory, Attention/Vigilance, and MCCB total scores in the FEPS (P < 0.05). Brain cortical thickness had positive moderating effects on cognitive impairment in FEPS with high HCY after controlling for sex, age, and education (P < 0.05). In HCs with high HCY, brain cortical thickness had no mediating or moderating effects on cognitive impairment. Compared with HCs, FEPS had thinner grey matter thickness, furthermore, the grey matter thickness might play a crucial role in relationship between high HCY and cognitive deficits.
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Inflammation is increasingly implicated as a risk factor for dementia, stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. We systematically reviewed the existing literature on the associations between markers of inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health, cerebrovascular disease, or cognitive impairment. Based on distinctions made in the literature, markers of inflammation were classified as systemic inflammation (e.g. C-reactive protein, interleukin-6, fibrinogen) or vascular inflammation/endothelial dysfunction (e.g. homocysteine, von Willebrand factor, Lp-PLA2). Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular inflammation, especially amongst stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD. Conversely, cross-sectional findings on systemic inflammation were mixed, although longitudinal investigations demonstrated that elevated levels of systemic inflammatory markers at baseline predicted subsequent SVD severity and progression. Importantly, regional analysis revealed that systemic and vascular inflammation were differentially related to two distinct forms of SVD. Specifically, markers of vascular inflammation tended to be associated with SVD in areas typical of hypertensive arteriopathy (e.g., basal ganglia), while systemic inflammation appeared to be involved in CAA-related vascular damage (e.g., centrum semiovale). Nonetheless, there is insufficient data to establish whether inflammation is causal of, or secondary to, SVD. Findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated neurodegenerative diseases.
The C677T Variant in MTHFR Modulates Associations Between Brain Integrity, Mood, and Cognitive Functioning in Old Age
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Our tensor-based morphometry analyses also showed significant associations between the C677T variant and reduced volumes in periventricular regions. A decrease in the size of periventricular structures allows the ventricles to expand; thus, this finding appears consistent with prior reports of an association between plasma homocysteine level and ventricular enlargement in older adults (59,60). However, this result should be interpreted with caution.
The C677T functional variant in the methylenetetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood homocysteine levels. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression.
Three-dimensional magnetic resonance imaging data were analyzed from 738 individuals (aged 75.5 ± 6.8 years; 438 men, 300 women), including 173 patients with Alzheimer’s disease, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer’s Disease Neuroimaging Initiative.
We found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine level mediates the association between MTHFR genotype and lower medial orbitofrontal volumes and that these volumes mediate the association between cognitive decline and depressed mood in this elderly cohort. We additionally show that vitamin B₁₂ deficiency interacts with the C677T variant in the etiology of hyperhomocysteinemia.
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Homocysteine and cognition: A systematic review of 111 studies
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Elevated plasma homocysteine (Hcy) levels have been associated with cognitive dysfunction in a wide range of conditions. The aim of this review is to establish which cognitive domains and populations are the most affected.
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We found 111 pertinent articles. There were 24 cohort studies, 18 randomized trials, 21 case-control studies, and 48 cross-sectional studies. This review reveals a positive trend between cognitive decline and increased plasma Hcy concentrations in general population and in patients with cognitive impairments. Results from the meta-analyses also confirm this trend. Treatment with vitamin supplementation fails to show a reduction in cognitive decline.
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View all citing articles on Scopus

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Regular Research ArticleAssociations Between Elevated Homocysteine, Cognitive Impairment, and Reduced White Matter Volume in Healthy Old Adults

Objectives

Methods

Results

Conclusion

Section snippets

Participants

Results

Discussion

Am J Clin Nutr

Am J Clin Nutr

Neurosci Lett

Am J Clin Nutr

Neuroimage

J Psychiatr Res

Neuroimage

Psychiatry Res

Am J Clin Nutr

Am J Clin Nutr

Am J Pathol

Lancet

Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

N Engl J Med

Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study

Ann Neurol

Homocysteine, white matter hyperintensities, and cognition in healthy elderly people

Ann Neurol

Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study

Arch Neurol

Homocysteine and brain atrophy on MRI of non-demented elderly

Brain

Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam Scan Study

Ann Neurol

Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men

Arch Neurol

Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study

Stroke

Vitamin B12 status and rate of brain volume loss in community-dwelling elderly

Neurology

Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study

Arch Neurol

Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. Clinical Gerontology: A Guide to Assessment and Intervention

Regular Research Article
Associations Between Elevated Homocysteine, Cognitive Impairment, and Reduced White Matter Volume in Healthy Old Adults

Vitamin B₁₂ status and rate of brain volume loss in community-dwelling elderly