Chapter 6. Summary, Conclusions and Future direction
6.3 Clinical implications
Our study provided the evidence that Hcy may be associated to small vessels disease and may influence microvascular system related perfusion in the brain. The decrease of cerebral perfusion not only leaded to white matter lesions but also contributed to cognitive impairment. Those findings confirmed the previous reports about the inverse relationship between Hcy and cognitive function. Hcy-lowering therapy, though was not effective to the cognitive function in patients with Alzheimer’s dementia, but it may be beneficial to vascular dementia.
Lack of association of Hcy and stroke may be related to the different pathogenesis from different subtypes of ischemic stroke and different effects of Hcy on subtypes of stroke. Our study supported the relationship of Hcy with small vessel disease and this finding was consistent with Japanese reports. People with ischemic stroke from small vessels or lacunar infarction or with massive white matter lesions need to be evaluated the serum levels of Hcy. Further dietary suggestion or Hcy-lowering therapy may be indicated for prevention of recurrent stroke.
In the prospective cohort study, we confirmed the relationship of Hcy with risk of CHD and mortality, especially cardiovascular death. Besides, we also provided optimal cutpoints of homocysteine in clinical prediction, which has never been reported before.
Subjects with serum Hcy level more than 9.5 µmol/L may be at high risk of CHD, while people with serum Hcy more than 11.8 µmol/L may have higher risk of mortality in the future years. We proposed a new definition of “hyperhomocysteinemia” for clinical practice. With such new definition, we can highlight the high risk population, and advise Hcy-lowering food or therapy for primary prevention from vascular disease and
mortality.
6.4 Conclusions
In conclusion, we found that the Hcy had no significant effect on the hemodynamic change on the large extracranial cerebral arteries. Such findings are different from the Hcy effects on the coronary flow. Investigating on the intracranial cerebral artery and further prospective studies are needed to confirm the role of Hcy on the hemodynamic flow of the brain.
We found that Hcy was significantly associated with cerebral white matter lesions (WML). After adjustment for known cardiovascular risk factors, Hcy and age remained as independent risk factors for the risk of WML. These findings suggest that Hcy had clinical utility in terms of identifying patients at increased risk of WML. This findings indicated that the effects of Hcy on the brain may be related to cerebral
microangiopathy and resulting to cerebral WML, and then further related to future cerebral vascular insults and cognitive impairment.
Individuals with higher level of Hcy had a significant higher risk of future CHD and all-cause of death. The optimal cutpoints of Hcy were 9.47 μmol/L for CHD and 11.84 μmol/L for death. Adding Hcy to the model that included the established risk factors improved the prediction for CHD and death among asymptomatic ethnic Chinese. The feasibility of incorporating Hcy in clinical screening for primary prevention warrants further research.
The randomized controlled trial demonstrates that multi-vitamin supplements can decrease plasma homocysteine concentration in patients with mild to moderate
Alzheimer’s disease and with normal serum levels of vitamin B12 and folic acid.
However, the study did not support the hypothesis that a reduction of plasma
homocysteine level can improve the cognitive function. Furthermore, multi-vitamin supplements had no statistically significant beneficial effects on both cognition and
daily living function.
6.5 Future research directions
(1) In addition to study on the hemodynamic status, research evaluating the relationship between Hcy and the hemorheology factor such as blood viscosity may be indicated.
(2) Our studies demonstrated the effect of Hcy on the brain may be mediated through microvascular system, further brain perfusion study such as perfusion CT with calculating the mean transit time of small cerebral vessels may be indicated for further exploring the effect Hcy on the intracranial perfusion and white matter lesions.
(3) Further grading on the WML in our study participants is indicated for comparison the relationship between Hcy levels and severity of cerebral WML.
(4) Longitudinal study for comparing the development of WML in subjects with high and low levels of Hcy is important since WML plays a role in future stroke and cognitive performance.
(5) The strong association of Hcy with the risk of future CHD and death indicated that Hcy still play an important role on the vascular disease. In further prospective studies, the subtypes of ischemic stroke, such as large vessel atherosclerotic infarcts, lacunar infarcts, embolic infarcts, and ischemic stroke of unknown or other origin should be specified since Hcy may have different impacts on different subtype of stroke.
(6) Since the mechanisms of stroke are heterogeneous and complicated, further randomized controlled trials of homocysteine-lowering therapy are needed in prevention of specified subtype of stroke such as small vessel infarcts or lacunar infarcts with leukoaraiosis.
(7) Further large randomized controlled trials with longer periods of homocysteine-lowering therapy are needed for people with vascular dementia.
(8) Our study participants were in the mild or moderate stage of dementia.
The clinical effects of vitamin therapy may be little or not obvious on such irreversible and significant damage of brain. Further study with selection of target participants with mild cognition impairment and very early stage of dementia may be indicated for further exploring the efficacy of
Hcy-lowering therapy on Alzheimer’s dementia.
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