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Current Issues
Table 1: Factors to Be Considered When Planning or Interpreting Studies on the Effect of Homocysteine-lowering
Treatment on Cognitive Function
Factor Explanation
Age at starting the treatment Dementia at younger age has different aetiological factors, such as ApoE genotype, Down’s syndrome and APP mutations. No medication has
been proved to treat genetically determined dementia.
Gender Oestrogen protects against dementia; post-menopausal women have a greater risk of dementia than men.
70
Sample size Most studies included a small number of subjects.
Progression of cognitive function MCI progresses to dementia at a rate of approximately 20% within two years of follow-up.
5
Showing no improvement of cognition after vitamin treatment might reflect arresting the progression of the disease.
Start of the treatment Supplement may be more effective if started earlier than the clinical onset of dementia.
Type of dementia and having In AD, almost all kinds of treatment have failed to reverse the accumulation of amyloid beta and neurofibrillary tangles.
dementia at the beginning of In vascular dementia, the role of Hcy-lowering treatment in secondary prevention of vascular disease is currently being debated. However, the
the treatment role of B vitamins in primary prevention of vascular pathologies has not been sufficiently investigated in clinical studies.
Duration of the treatment Dementia is a disease that takes decades to develop; therefore, treatment is not expected to influence it within a few months. Several years
(more than five) may be necessary to prevent MCI or to prevent the progression of MCI to AD.
Medications (statins, indomethacine, Cholesterol-lowering treatment, commonly used in elderly people, and indomethacine are drugs that have been shown to influence
omega-3 fatty acids, antioxidants) neurodegenerative proteins or functional enzymes. The interaction with B vitamins has not been investigated.
Baseline Hcy Only subjects with elevated Hcy or low status of the B vitamins are expected to benefit from supplementation.
Doses and forms of the vitamins Approximately 0.8mg folate, 0.5mg vitamin B
12
and 10mg vitamin B
6
daily might be necessary, especially in elderly people, who may have
malabsorption. A combination seems to be more effective in lowering Hcy than a single vitamin.
Folinic acid is readily available to the brain. Methylcobalamin is a ready-to-use co-factor and may thus be more effective than other available
forms of the vitamin.
Different domains of cognition may Different domains of cognition and brain function (memory, dementia, language, abstract thinking) may show different response owing to the
be differently affected effect of Hcy lowering on different functional pathways in the brain.
Population-specific factors Folate fortification may account for less response in studies conducted on fortified populations.
Racial differences may be related to a different risk profile.
Tests used for estimating These tests are extremely variable between the studies, not standardised, in most cases not comparable between the studies and not sensitive
cognitive function and specific enough to detect small variations.
ApoE = apolipoprotein E; APP = amyloid precursor protein; MCI = mild cognitive impairment; AD = Alzheimer’s disease; Hcy = homocysteine.
Epidemiologic Follow-up Study III in the highest quartile of Hcy of the primary outcomes was stroke. An approximately 25% reduction in
compared with the lowest quartile.
24
In the Framingham Offspring the risk of stroke was found in the supplement group compared with the
Study, elevated concentration of Hcy was a risk factor for silent placebo group (relative risk 0.75, 95% CI 0.59–0.97; p=0.03).
28
cerebral infarcts in 2,040 people free of clinical stroke who were
tested by MRI.
25
The OR for silent cerebral infarcts for plasma Hcy was There is currently no consensus on using B vitamins for primary or
2.23 (p<0.001), which exceeded that for hypertension, cholesterol, secondary prevention of stroke. Nevertheless, the American Stroke
diabetes and other common risk factors.
25
Association Stroke Council reiterates the importance of meeting
current recommended daily intakes of the vitamins.
31
Because the relationship between Hcy elevation and stroke suggests a
causal relationship, several trials have been started to test the effect of Hcy Homocysteine and Other Brain Lesions
lowering on stroke prevention. Several studies have shown that risk of In a recently published report from the Framingham Offspring Study,
stroke may be slightly but significantly reduced by B vitamins. In a 1,965 middle-aged adults (mean age 61 years) who were free of
population-based study, Yang et al.
26
reported a decline in stroke-related stroke, dementia or neurological disorders were tested for their Hcy
mortality after folic acid fortification in the US and Canada that was and MRI brain measurements.
25
Higher plasma Hcy levels were
stronger than that found in England and Wales during the same period.
26
strongly and independently associated with lower brain volume and
Moreover, folic acid and vitamin B
6
lowered Hcy and caused slight the presence of silent brain infarcts in healthy subjects.
32
improvement in cerebrovascular and cerebral indices.
27
Furthermore, the
risk of stroke was lowered in a five-year treatment trial on subjects Homocysteine has been related to several brain lesions that were
receiving either placebo or folic acid 2.5mg plus vitamin B
6
50mg and B
12
estimated quantitatively or semi-quantitatively by MRI. In the Rotterdam
1mg (relative risk 0.75, 95% CI 0.59–0.97; p=0.03).
28
In a two-year trial, Scan Study, Hcy was related to white matter lesions.
33
Moreover, in non-
high doses of B vitamins (vitamin B
6
25mg, vitamin B
12
0.4mg and folic demented people 60–90 years of age, lower hippocampal volumes were
acid 2.5mg) were compared with low doses (vitamin B
6
200µg, vitamin B
12
found in subjects with higher Hcy compared with those with lower
6µg and folic acid 20µg) in secondary prevention of stroke.
29
The effect of Hcy.
34
This was confirmed by another study on elderly people.
35
treatment on stroke risk was not significant during this trial. Nevertheless, Moreover, the degree of cortical atrophy increased with increasing
a 21% reduction in the combined risk of stroke, coronary disease and Hcy.
34
These results suggest that keeping Hcy low might delay brain
death was observed in a subgroup of this study population that included shrinkage with age and the progression of silent brain infarcts.
patients who were likely to benefit from treatment.
30
In the Heart
Outcomes Prevention Evaluation (HOPE) 2 study, 5,522 patients with Homocysteine in Patients with Parkinson’s Disease
vascular disease or diabetes were randomised to receive placebo or folic Parkinson’s disease (PD) is the second most common neurodegenerative
acid 2.5mg plus vitamin B
6
50mg and vitamin B
12
1mg for five years; one disease in elderly people, after dementia. PD is characterised by
12 EUROPEAN NEUROLOGICAL REVIEW
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