**1.1 Subarachnoid haemorrhage**

Subarachnoid haemorrhage (SAH) is caused by rupture of intracranial aneurysms [1, 2]. Approximately 5–15% of the stroke patients have ruptured intracranial aneurysms [3, 4].

Aneurysmal SAH leads to a prolonged hospital stay [1]. Therefore, aneurysmal subarachnoid haemorrhage results in a significant financial burden in the USA [1]. In addition, aneurysmal SAH causes approximately 45% mortality in 30 days [3, 5]. As many as 30% of the patients who survived the SAH had moderate to severe neurological deficit and disability [3, 5].

#### **1.2 Intracranial aneurysms**

Saccular intracranial aneurysms are abnormal focal outpouchings of cerebral arteries [3]. The prevalence of intracranial aneurysms in the adult population in the USA is 1–5% [3, 6]. Most of the intracranial aneurysms are small [3]. Approximately 50–80% of all the intracranial aneurysms do not rupture [3, 7].

Intracranial aneurysms are usually sporadically acquired lesions [3]. A rare familial form is present, and this is associated with conditions such as cerebral arteriovenous malformations (AVMs), autosomal dominant polycystic kidney disease (ADPKD), fibromuscular dysplasia, Marfan syndrome and Ehlers-Danlos syndrome [3, 5]. Multiple genetic susceptibilities may be acting synergistically in the development of SAH [5, 8]. The increase in the familial risk of developing SAH is nearly four times higher among first-degree relatives [5, 9, 10].

Unruptured aneurysms can potentially result in cranial nerve palsies such as third cranial nerve palsy and rarely brainstem compression [3, 7, 11]. These patients have a higher risk of rupture of intracranial aneurysm [3, 7]. They have an annual risk of aneurysmal rupture of about 6% [3, 12].

#### **1.3 Homocysteine**

Homocysteine is an endogenous, nonstructural protein which contains sulphur [13]. Homocysteine is involved in the metabolism pathway of methionine and cysteine [13, 14]. Homocysteine can be irreversibly degraded to cysteine via the trans-sulphuration pathway or remethylated back to methionine [15]. The biochemistry of methionine is regulated by the enzymes controlling homocysteine concentration [15]. An elevated level of serum homocysteine is the intermediate product of methionine metabolism [16].

In addition, the metabolism of homocysteine is dependent on nutritional factors comprising of vitamin B12 and folic acid [16, 17]. A reduction in the levels of vitamin B12 and folic acid causes an increase in serum homocysteine levels [16]. Homocysteine also plays an important role in the metabolism of folic acid and catabolism of choline which are both vital for the regulation of methionine [15]. Homocysteine is very important for the cellular homeostasis [15].

Normal level of total concentration of homocysteine in plasma of healthy people is between 5.0 and 15.0 mmol/l. [13] Raised serum homocysteine is an independent risk factor for cardiovascular diseases [13, 15, 18]. Elevated serum homocysteine is associated with a rise in morbidity and mortality [18, 19].

An increase in serum homocysteine results in oxidative stress and systemic inflammation which in turn leads to an accelerated telomere shortening [13, 19]. Furthermore, elevated serum homocysteine damages endothelial cells [13]. As a result, the blood vessels are less flexible and the process of haemostasis is disturbed [13]. **An increase in serum homocysteine can be treated by folic acid, vitamin B12 and vitamin B6 supplements** [13, 15].

#### **2. Homocysteine and intracranial aneurysm**

Ren et al. conducted a study on the Han Chinese patients with intracranial aneurysm who were admitted to the hospital [17]. In this study, the mean serum total homocysteine level in the patient group with intracranial aneurysm was significantly higher than those in the control group [17]. In addition, homocysteine had an adjusted odds ratio of 2.196 (*P* = 0.012) for the development of intracranial aneurysm [17].

**39**

*Serum Homocysteine and Intracranial Aneurysms DOI: http://dx.doi.org/10.5772/intechopen.88570*

the development of atherosclerosis [20].

**3. Polymorphism**

sis [5, 21, 22].

cranial aneurysms [5, 8].

ment in Xu et al.'s study [20].

and not a direct cause of intracranial aneurysm [17].

Furthermore, raised serum homocysteine was reported to be an independent risk factor for development of intracranial aneurysms [17]. Ren et al. proposed that homocysteine should be seen as an indicator of the risk of intracranial aneurysm

In the same study, an association between serum total homocysteine and folate and vitamin B12 in the patients with intracranial aneurysm was present [17]. The serum total homocysteine level was negatively correlated with folate and vitamin B12 levels in the study by Ren et al. [17] Folic acid and vitamin B12 are therefore found to be protective against formation of intracranial aneurysms [17]. This is due to the roles of vitamin B12 and folic acid in the regulation of the metabolism of homocysteine [17]. In a previous study, insufficient plasma level of one or more B

In the study conducted by Xu et al., homocysteine increases the development of intracranial aneurysms in rats, possibly by the different effects on the expression of molecules which are essential for vascular wall modeling [20]. The formation of

Interestingly, polymorphism of the genes coding for the various components of the vessel walls has been proposed to be associated with the development of intra-

Polymorphisms involving homocysteine metabolism can also promote formation of abdominal aortic aneurysms, dissection of the cervical arteries and atherosclero-

Moreover, the expression of matrix metalloproteinase-2 (MMP-2), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and MMP-2 in the walls of intracranial aneurysm was increased by methionine treat-

Furthermore, autosomal recessive deficiency in cystathionine-synthase is involved in homocysteine metabolism [5, 23]. This deficiency in cystathioninesynthase presents together with the development of intracranial aneurysms [5, 23]. In the study by Semmler et al., polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms [5]. The G-allele of RFC1c.80G→A and the insertion allele of DHFRc.594 + 59del19bp polymorphisms may result in intracranial aneurysm formation [5]. The G-allele of the missense polymorphism Tc2c.777C→G may protect from the development of intracranial aneurysm [5]. This G-allele of the Tc2c.777C→G polymorphism has been reported to affect the vitamin B12 binding affinity and the ability to transport vitamin B12 into tissues [5, 24–26]. This causes a decrease in remethylation of homocysteine to

Impairment of homocysteine metabolism may lead to an accumulation of asymmetric dimethylarginine [27, 28]. Asymmetric dimethylarginine.is a major

methionine by vitamin B12-dependent MTR [5, 24–26].

**4. Role of nitric oxide in homocysteine metabolism**

Endothelial damage is one of the early changes in the walls of intracranial aneurysms resulting from inflammation [20]. An increase in serum homocysteine has been reported to damage the vascular endothelium [20]. This in turn leads to

vitamins may potentially result in high levels of serum homocysteine [16].

intracranial aneurysms is associated with chronic inflammation [20].

*Serum Homocysteine and Intracranial Aneurysms DOI: http://dx.doi.org/10.5772/intechopen.88570*

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

50–80% of all the intracranial aneurysms do not rupture [3, 7].

is nearly four times higher among first-degree relatives [5, 9, 10].

risk of aneurysmal rupture of about 6% [3, 12].

product of methionine metabolism [16].

Saccular intracranial aneurysms are abnormal focal outpouchings of cerebral arteries [3]. The prevalence of intracranial aneurysms in the adult population in the USA is 1–5% [3, 6]. Most of the intracranial aneurysms are small [3]. Approximately

Intracranial aneurysms are usually sporadically acquired lesions [3]. A rare familial form is present, and this is associated with conditions such as cerebral arteriovenous malformations (AVMs), autosomal dominant polycystic kidney disease (ADPKD), fibromuscular dysplasia, Marfan syndrome and Ehlers-Danlos syndrome [3, 5]. Multiple genetic susceptibilities may be acting synergistically in the development of SAH [5, 8]. The increase in the familial risk of developing SAH

Unruptured aneurysms can potentially result in cranial nerve palsies such as third cranial nerve palsy and rarely brainstem compression [3, 7, 11]. These patients have a higher risk of rupture of intracranial aneurysm [3, 7]. They have an annual

Homocysteine is an endogenous, nonstructural protein which contains sulphur

[13]. Homocysteine is involved in the metabolism pathway of methionine and cysteine [13, 14]. Homocysteine can be irreversibly degraded to cysteine via the trans-sulphuration pathway or remethylated back to methionine [15]. The biochemistry of methionine is regulated by the enzymes controlling homocysteine concentration [15]. An elevated level of serum homocysteine is the intermediate

In addition, the metabolism of homocysteine is dependent on nutritional factors comprising of vitamin B12 and folic acid [16, 17]. A reduction in the levels of vitamin B12 and folic acid causes an increase in serum homocysteine levels [16]. Homocysteine also plays an important role in the metabolism of folic acid and catabolism of choline which are both vital for the regulation of methionine [15].

Normal level of total concentration of homocysteine in plasma of healthy people is between 5.0 and 15.0 mmol/l. [13] Raised serum homocysteine is an independent risk factor for cardiovascular diseases [13, 15, 18]. Elevated serum homocysteine is

An increase in serum homocysteine results in oxidative stress and systemic inflammation which in turn leads to an accelerated telomere shortening [13, 19]. Furthermore, elevated serum homocysteine damages endothelial cells [13]. As a result, the blood vessels are less flexible and the process of haemostasis is disturbed [13]. **An increase in serum homocysteine can be treated by folic acid, vitamin** 

Ren et al. conducted a study on the Han Chinese patients with intracranial aneurysm who were admitted to the hospital [17]. In this study, the mean serum total homocysteine level in the patient group with intracranial aneurysm was significantly higher than those in the control group [17]. In addition, homocysteine had an adjusted odds ratio of 2.196 (*P* = 0.012) for the development of intracranial aneurysm [17].

Homocysteine is very important for the cellular homeostasis [15].

associated with a rise in morbidity and mortality [18, 19].

**B12 and vitamin B6 supplements** [13, 15].

**2. Homocysteine and intracranial aneurysm**

**1.2 Intracranial aneurysms**

**1.3 Homocysteine**

**38**

Furthermore, raised serum homocysteine was reported to be an independent risk factor for development of intracranial aneurysms [17]. Ren et al. proposed that homocysteine should be seen as an indicator of the risk of intracranial aneurysm and not a direct cause of intracranial aneurysm [17].

In the same study, an association between serum total homocysteine and folate and vitamin B12 in the patients with intracranial aneurysm was present [17]. The serum total homocysteine level was negatively correlated with folate and vitamin B12 levels in the study by Ren et al. [17] Folic acid and vitamin B12 are therefore found to be protective against formation of intracranial aneurysms [17]. This is due to the roles of vitamin B12 and folic acid in the regulation of the metabolism of homocysteine [17]. In a previous study, insufficient plasma level of one or more B vitamins may potentially result in high levels of serum homocysteine [16].

In the study conducted by Xu et al., homocysteine increases the development of intracranial aneurysms in rats, possibly by the different effects on the expression of molecules which are essential for vascular wall modeling [20]. The formation of intracranial aneurysms is associated with chronic inflammation [20].

Endothelial damage is one of the early changes in the walls of intracranial aneurysms resulting from inflammation [20]. An increase in serum homocysteine has been reported to damage the vascular endothelium [20]. This in turn leads to the development of atherosclerosis [20].

### **3. Polymorphism**

Interestingly, polymorphism of the genes coding for the various components of the vessel walls has been proposed to be associated with the development of intracranial aneurysms [5, 8].

Polymorphisms involving homocysteine metabolism can also promote formation of abdominal aortic aneurysms, dissection of the cervical arteries and atherosclerosis [5, 21, 22].

Moreover, the expression of matrix metalloproteinase-2 (MMP-2), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and MMP-2 in the walls of intracranial aneurysm was increased by methionine treatment in Xu et al.'s study [20].

Furthermore, autosomal recessive deficiency in cystathionine-synthase is involved in homocysteine metabolism [5, 23]. This deficiency in cystathioninesynthase presents together with the development of intracranial aneurysms [5, 23].

In the study by Semmler et al., polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms [5]. The G-allele of RFC1c.80G→A and the insertion allele of DHFRc.594 + 59del19bp polymorphisms may result in intracranial aneurysm formation [5]. The G-allele of the missense polymorphism Tc2c.777C→G may protect from the development of intracranial aneurysm [5]. This G-allele of the Tc2c.777C→G polymorphism has been reported to affect the vitamin B12 binding affinity and the ability to transport vitamin B12 into tissues [5, 24–26]. This causes a decrease in remethylation of homocysteine to methionine by vitamin B12-dependent MTR [5, 24–26].

#### **4. Role of nitric oxide in homocysteine metabolism**

Impairment of homocysteine metabolism may lead to an accumulation of asymmetric dimethylarginine [27, 28]. Asymmetric dimethylarginine.is a major endogenous inhibitor of nitric oxide (NO) and is a good predictor of early cardiovascular diseases and mortality [27–30]. In addition, the availability of NO is a major requirement for the development of intracranial aneurysms [5, 31].

In an animal study conducted in rodents, the development of intracranial aneurysm was prevented by inhibition of nitric oxide synthase (NOS) [5, 31]. Inducible nitric oxide synthase (iNOS) is expressed in human and rat cerebral aneurysms [2]. In another animal study, the size of intracranial aneurysms is significantly smaller in the mice with iNOS compared to the mice without iNOS [2, 5].

Aminoguanidine is a relatively selective inhibitor of iNOS [2]. Aminoguanidine reduces the number of the aneurysms in rats [2]. In the study by Sadamasa et al., iNOS possibly has management potential in the prevention of the progression of cerebral aneurysms, though it is not necessary for the initiation of cerebral aneurysm [2].

However, in another study, there was no association between homocysteine and intracranial aneurysms. Notably, this study was conducted comparing a case group (patients with intracranial aneurysms) with a control group consisting of patients with arteriovenous malformation (AVM) as well as no aneurysms [14].
