Is homocysteine a causal and treatable risk factor for vascular diseases of the brain (cognitive impairment and stroke)?

In this issue, Vermeer et al. report a significant, independent association between increasing plasma concentrations of total homocysteine (tHcy) and brain magnetic resonance imaging (MRI) evidence of periventricular and subcortical white matter lesions (“leukoaraiosis”) and silent brain infarcts (focal hyperintensities 3mm in size on T2 images). Their report is based on a cross-sectional, population-based study of 1,077 people ages 60–90 years. Because these brain lesions are usually areas of ischemic demyelination due to intracranial small vessel disease, the results of this and another recent study support the “homocysteine hypothesis” that homocysteine is a causal risk factor for atherosclerotic cerebrovascular disease. Furthermore, they endorse the exciting prospect that lowering plasma tHcy concentrations by means of multivitamin therapy (folic acid, vitamin B12, and vitamin B6) 6 may reduce the burden of cognitive impairment and stroke caused by atherosclerotic cerebrovascular disease. However, before leaping to this attractive conclusion and routinely screening our patients (and ourselves) for high tHcy, prescribing them (and ourselves) multivitamin therapy, and lobbying public health physicians and governments for the fortification of food with folic acid (or higher doses of it), there are several issues to consider. The first issue concerns the diagnosis of white matter lesions and silent brain infarcts by MRI. Is it reliable, and is it a valid surrogate diagnosis for brain ischemia and cognitive impairment? White matter disease is notoriously difficult to quantify, as attested to by the presence of more than a dozen scales, none of which have been validated against morphological studies and few of which have been evaluated for interobserver and intraobserver reliability. However, a notable strength of the Rotterdam Scan Study was its use of two independent raters who were able to achieve excellent interrater agreement for white matter lesion load. The validity of an MRI diagnosis of white matter lesions and silent brain infarcts as a sign of ischemic demyelination of white matter due to intracranial smallvessel disease is supported by pathological studies, epidemiological studies, and even clinical trials. However, leukoaraiosis is not always caused by ischemia, and when it is, it is not always caused by “hypertensive” small-vessel hyaline arteriolosclerosis; it can also be caused by microatheroma, lipohyalinosis, fibrinoid necrosis, amyloid angiopathy, or, rarely, arteritis, granular or eosinophilic material in the arterial wall (cerebral autosomal dominant subcortical infarcts and leukoencephalopathy), or platelet emboli. This has been verified by epidemiological studies that have revealed increasing age and high blood pressure as the most important, but not the sole or essential, risk factors for leukoaraiosis. Indeed, only about 25% of elderly patients with severe hypertension develop severe white matter changes. Other classic vascular risk factors also have a role, as may genetic factors; forced expiratory volume; and plasma concentrations of fibrinogen, vitamin E, coagulation factor VIIc, and now tHcy. The potential role of tHcy in leukoaraiosis, an important cause of vascular cognitive impairment, underpins the remaining issues to consider. The first is that standardization of the assay for plasma tHcy is rudimentary compared with that for measurements such as cholesterol. Most analyses of tHcy using high-performance liquid chromatography, the most widely used method, have similar distributions and reference ranges but imprecise estimates; the imprecision is related in part to instability of the standard commonly used for calibration. The second issue is whether elevated plasma tHcy is a causal risk factor for intracranial small-vessel and other types of cerebrovascular disease, and, if so, in which types of patients (eg, perhaps only high risk groups); whether it is a causal risk factor for thrombosis, irrespective of vascular disease; or whether it is simply a marker of another causal factor (eg, perhaps low vitamin B status), or even a product or marker of injury to the brain or blood vessels. The points in favor of a causal relationship between tHcy and cerebrovascular disease are as follows: