Homocysteine and progression of generalized small-vessel disease

Kloppenborg, Raoul P.; Geerlings, Mirjam I.; Visseren, Frank L.J.; Mali, Willem P.Th.M.; Vermeulen, Michel; Graaf, Yolanda van der; Nederkoorn, Paul J.

doi:10.1212/wnl.0000000000000168

Cited by 65 publications

(43 citation statements)

References 31 publications

(28 reference statements)

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“…CVD-induced cognitive impairment is primarily associated with microvascular disease, which reduces blood flow to white matter, and has been shown to significantly increase white matter atrophy and ischemic white matter changes in HHcy patients and in cognitively normal adults, 55 years and older, with CVD [19,20]. Cortical atrophy is also linked to microvascular disease.…”

Section: Primary Outcomesmentioning

confidence: 99%

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

Shankle¹,

Hara²,

Barrentine

et al. 2016

JAD

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Abstract. We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin ® /CerefolinNAC ® (CFLN: Lmethylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [ ± σ] = 18.6 ± 16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [ ± σ] = 12.6 ± 5.6 months). Thirtyseven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [ ± σ] = 13.3 ± 17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

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Section: Primary Outcomesmentioning

confidence: 99%

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

Shankle¹,

Hara²,

Barrentine

et al. 2016

JAD

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“…The association with hippocampal atrophy appears to be independent of amyloid pathology [14]. White matter lesions reflect vascular damage [92] and it is therefore notable that white matter changes are associated with HHCy [47,49,64,94] and with low vitamin B 12 levels [21] and low folate [51,100]. Evidence supporting a causal relationship between HHCy and cerebrovascular injury includes: i) independent, graded association of HHCy with stroke in prospective and retrospective clinical studies [48,61]; ii) genetic association studies of genes regulating HCy metabolism, using Mendelian randomisation [9]; iii) HHCy-induced lesions in experimental animals [4,68,108,111].…”

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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“…Hyperhomocysteinemia is thought to affect the hippocampus more strongly than any other part of the brain. It has been recently reported that hyperhomocysteinemia affects the cerebral smaller vessels more than major vessels [19]. Blood of hippocampal region is supplied via the anterior choroidal artery, which arises from distal to the bifurcation of the posterior communicating artery, and is classified as a perforator branch.…”

Section: Discussionmentioning

confidence: 99%

Correlation of hippocampal atrophy with hyperhomocysteinemia in hemodialysis patients: An exploratory pilot study

et al. 2017

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BackgroundCognitive impairment is one of the important critical issues in hemodialysis (HD) patients. However, the associating factors of brain atrophy in HD patients have not been fully elucidated.Purpose and methodsBrain magnetic resonance imaging (MRI) was performed in 34 of total 72 HD outpatients in our dialysis center. These MRI images were analyzed by an application software; Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD). VSRAD quantitatively calculates the extent of brain atrophy (percent of volume reduction) comparing with a MRI imaging database of 80 age-matched healthy controls. The extent of both hippocampal and whole-brain atrophy was evaluated with possible contributing factors.ResultsIn all patients, the mean extent of hippocampal atrophy was 27.3%, and the mean extent of whole-brain atrophy was 11.2%. The extent of hippocampal atrophy was significantly correlated with low body mass index (BMI), total serum homocysteine (tHcy) levels, and brachial-ankle pulse wave velocity (baPWV). The extent of whole-brain atrophy showed significant correlations with age, hypoalbuminemia, and baPWV. Based on the multiple regression analysis, tHcy was an independent determinant of hippocampal atrophy (β = 0.460, R2 = 0.189, P<0.01); while age was an independent determinant of whole-brain atrophy (β = 0.594, R2 = 0.333, P<0.01).ConclusionsIn this exploratory pilot study, hippocampal atrophy was significantly correlated with hyperhomocysteinemia in HD patients.

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Homocysteine and progression of generalized small-vessel disease

Abstract: Our findings implicate a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney are affected.

Cited by 65 publications

References 31 publications

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

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

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

Correlation of hippocampal atrophy with hyperhomocysteinemia in hemodialysis patients: An exploratory pilot study

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