Hisanori Kowa

Migraine and MTHFR C677T genotype in a population-based sample

Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype status.

The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine

Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:762-764, 2000.

Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD

To the Editor: The paper by Yasui et al.1 showing elevated plasma homocysteine levels in levodopa-treated patients with PD is interesting and confirms other reports2 and our unpublished findings (table). It also shows that patients with the TT-genotype of the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) have especially high homocysteine levels. These findings have to be related to the metabolism of levodopa and methyl groups and may have importance in the future treatment of PD with levodopa. Homocysteine is the demethylated derivative of methionine and is only formed in numerous transmethylation reactions (e.g., catecholamine O-methyltransferase [COMT]) that use S-adenosylmethionine (SAM) as the methyl donor.3 Most administered levodopa is COMT-methylated to 3O-methyldopa and the methylation of 1000 mg of levodopa consumes 5 mMol of SAM methyls and produces 5 mMol of S-adenosylhomocysteine (SAH), which then is deadenosylated to homocysteine. In the study of Yasui et al., the average levodopa dose was 1500 mg. Therefore, it is most likely that levodopa treatment contributed to hyperhomocysteinemia in their patients with PD. In this context it is important to note that humans normally consume about 15 mMol/day of SAM methyls for methylation of endogenous compounds such as phospholipids, DNA, myeline, and proteins. About 10 mMol of these methyls are supplied from food, mainly as methionine and choline, and about 5 mMol are de novo synthesized in one-carbon (folate) metabolism and are transferred by a vitamin B12-dependent reaction to homocysteine, again forming methionine and SAM.4 As we can assume that levodopa-treated PD patients do not increase their intake of labile methyls, they must de novo synthesize all their extra methyls consumed for levodopa methylation. In the above 1000 mg example, the patient must increase his or her de novo synthesis of methyls by about 100%. If methyl neogenesis is hampered by poor folate intake, especially if the patient is a TT-homozygote for C677T/MTHFR polymorphism (about 12% of the Caucasian population), or has a low vitamin B12 level, production of SAM methyls may not be sufficient for both methylation of endogenous compounds and levodopa. This may lead to hypomethylation of essential neural components, and might explain the neuropsychiatric symptoms in folate and vitamin B12 deficiency.5 This mechanism may contribute to side effects of levodopa. If this is the case, early combination of levodopa with COMT inhibitors (tolcapone, entacapone) would prove to be beneficial. Moreover, studies on the relationship between complications to levodopa therapy in PD and homocysteine, folate, vitamin B12, and C677T/MTHFR genotypes are warranted.Plasma homocysteine and cysteine levels were measured in 90 patients with PD with the MTHFR C677T (T/T) genotype. The authors found that the levels of homocysteine-a possible risk factor for vascular disease-were elevated by 60% in levodopa-treated patients with PD, with the most marked elevation occurring in patients with the T/T genotype. Cysteine levels in subjects with PD did not differ from levels in control subjects. In the T/T genotype patients, homocysteine and folate levels were inversely correlated. Increased homocysteine might be related to levodopa, MTHFR genotype, and folate in PD.

Population-based door-to-door survey of migraine in Japan: The Daisen Study

Objectives.—To determine prevalence and characteristics of migraine in Japan, and to investigate use of medical care and whether food preference is associated with risk of migraine.

Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura

Recently, several angiotensin I-converting enzyme (ACE) inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. ACE is one of the key enzymes in the rennin-angiotensin-aldosterone system, which modulates vascular tension and blood pressure. In humans, serum ACE levels are strongly genetically determined. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity levels. To investigate the role of ACE polymorphism in headache, we analyzed the ACE insertion (I)/deletion (D) genotypes of 54 patients suffering from migraine with aura (MwA), 122 from migraine without aura, 78 from tension-type headache (TH), and 248 non-headache healthy controls. The ACE D allele were significantly more frequent in the MwA than controls (p<0.01). The incidence of the D/D genotype in MwA (25.9%) was significantly higher than that in controls (12.5%; p<0.01; odds ratio=5.26, 95% confidence interval: 1.69-16.34, adjusted for age and gender). No differences in the remaining groups were found. Our results support the conclusion that the D allele and the D/D genotype in the ACE gene is a genetic risk factor for Japanese MwA. There seems to be a possible relationship between ACE activity and the pathogenesis of migraine.

Increased plasma substance P and CGRP levels, and high ACE activity in migraineurs during headache-free periods

Abstract Substance P (SP), calcitonin gene‐related peptide (CGRP), and angiotensin converting enzyme (ACE) may have roles in trigeminovascular nociceptive mechanisms. We investigated interictal levels of SP, CGRP, ACE activity, and their correlation, in a sample of migraineurs. Forty‐one patients suffering from migraine with aura (MA), 54 without aura (MO), and 52 non‐headache subjects (controls) participated in this study. Blood samples were collected from cubital veins. Plasma levels of SP and CGRP were measured by enzyme immunoassay. Plasma ACE activities were measured spectrophotometrically. SP levels in MA (6.6 ± 3.7 pg/ml; mean ± SD) and MO (6.6 ± 3.2 pg/ml) were significantly higher than in controls (4.8 ± 2.4 pg/ml) (P < 0.01). CGRP levels in MA (18.8 ± 8.8 pg/ml) and MO (19.1 ± 9.4 pg/ml) were also significantly higher than in controls (13.4 ± 4.4 pg/ml) (P < 0.01). ACE activities in MA (34.6 ± 19.0 U/l) were significantly higher than in MO (25.3 ± 13.2 U/l) and controls (27.0 ± 20.4 U/l) (P < 0.05). There was a significant correlation between SP and CGRP levels (P < 0.05). In MA, SP and CGRP showed a tendency toward positive correlation, which was not significant. There was a weak, but significant positive correlation between SP levels and ACE activities (P < 0.01). However, a relationship between ACE activities and CGRP levels was not observed. The data suggest that SP, CGRP, and ACE are relevant to migraine pathophysiology, and that they may interact.

Hypertrophy of IMC of carotid artery in Parkinson's disease is associated with L-DOPA, homocysteine, and MTHFR genotype.

In recent years, an intense interest has developed in the association between Parkinsons disease (PD) and hyperhomocysteinemia. Homocysteine (Hcy) is a neuronal excitotoxic amino acid, and is well known as a risk factor for vascular diseases. Some reports suggest that the administration of L-DOPA may promote hyperhomocysteinemia and idiopathic atherosclerosis. In this study, we report that a mild hypertrophy of the intima-media complex (IMC) of the carotid artery, which has been established as a marker for systemic atherosclerosis, is observed in PD patients compared with normal subjects. PD patients that were treated with L-DOPA for long durations showed a hypertrophic IMC, while the patients that were not treated with L-DOPA did not show any hypertrophic changes in the IMC. These hypertrophic changes were observed primarily in patients with a Hoehn-Yahr stage of 3-5. PD patients with hypertrophic IMC of the carotid artery also exhibited elevated plasma levels of Hcy associated with the C677T genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR). Moreover, a prolonged duration of treatment with L-DOPA in patients with MTHFR T/T genotype enhanced the hypertrophy of IMC, compared with patients with the C/C or C/T genotype. These results suggest that hyperhomocysteinemia promoted by the C677T genotype of MTHFR and prolonged treatment with L-DOPA enhances atherosclerosis in PD patients and affects their general condition.

Levodopa‐induced hyperhomocysteinaemia in Parkinson's disease

Elevated plasma homocysteine (Hcy) has been observed in Parkinson’s disease (PD) in recent years (1, 2). It has been suggested that hyperhomocysteinaemia in PD patients may be associated with levodopa administration and with the methylenetetrahydrofolate reductase (MTHFR) C677T genotype (1). Hcy is well known as one of the risk factors for vascular diseases (3, 4). Furthermore, it may act as an excitotoxic amino acid in neuronal cells, and it is therefore important to manage Hcy levels during treatment for PD. To determine the effect of levodopa administration on secondary hyperhomocysteinaemia in different MTHFR genotypes, Hcy levels in de novo PD patients before and after levodopa treatment were investigated. This study included 20 de novo PD patients, all of whom were Japanese and had given their informed consent to this study, whose plasma Hcy concentrations were measured before levodopa treatment. All 20 PD patients were then administered several doses of levodopa, and plasma Hcy concentrations were measured again. Levodopa was administered as levodopa+carbidopa, at a daily dose of 235 115 mg (mean SD, range: 100–600). The duration of levodopa+carbidopa administration was 110 181 days (mean SD, range: 7–360). Plasma Hcy concentrations were measured by high performance liquid chromatography and the MTHFR genotype was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), as described previously (1, 5). Hcyconcentrationsbefore levodopaadministration in the 20 de novo PD patients (11.0 4.5 nmol/ml) did not differ significantly compared with control subjects (10.2 5.3 nmol/ml). However, Hcy concentrations were significantly elevated after levodopa administration (18.8 13.5 nmol/ml, P < 0.001 vs control subjects, ANOVA). In all but one patient, Hcy concentrations were elevated after levodopa administration. In order to investigate the association between the increase in Hcy concentrations following levodopa treatment and MTHFR C677T genotype, patients were classified into three groups according to their MTHFR genotypes. Six patients were C/C (wild), eight were C/T, and six were the T/T genotype. It is noteworthy that plasma Hcy concentrations greatly increased following levodopa treatment in patients with the T/T genotype, while those with the C/C or C/T genotypes showed only a slight increase. Hcy concentrations increased from 10.9 1.6 to 14.6 2.4 nmol/ml in the C/C genotype group, from 10.3 4.0 to 14.1 4.2 nmol/ml in the C/T group, and from 11.9 7.1 to 29.3 21.8 nmol/ml in the T/T group. Post-treatment Hcy concentrations in T/T genotype patients were higher than in the other genotype groups (P < 0.03, ANOVA). The relative increase in Hcy concentrations following levodopa administration was 35.0 21.3% (mean SD) for the C/C genotype, 44.8 36.7% for the C/T genotype, and 156.2 108.5% for the T/T genotype. The percentage increase in Hcy concentrations was higher in patients with the T/T genotype than in the other genotype groups

A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy.

Many clinical and pathological discussions have been focused on the difficulty of differential diagnosis between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) in recent years. This study was conducted to evaluate the usefulness of tau proteins in cerebrospinal fluid (CSF) for the differentiation of these two diseases. Subjects consisted of 10 patients with CBD (four males and six females with a mean age of 67.9+/-5.8 years), 12 patients with PSP (eight males and four females with a mean age of 62.6+/-5.8 years) and 36 control subjects (CTL) (16 males and 20 females with a mean age of 65.8+/-9.9 years). The CBD group included patients with probable CBD, while all the patients in the PSP group satisfied the diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP). CSF tau proteins were measured with the sandwich ELISA method (Innogenetics, Belgium). The CSF tau protein level was 320.1+/-86.5 pg/ml in the CBD group, 151.5+/-52.7 pg/ml in the PSP group and 128.7+/-91.7 pg/ml in the CTL group. Significant differences were noted in tau protein levels between the CBD group and both the PSP group (P<0.001) and the CTL group (P<0.005). We suggested that the measurement of CSF tau proteins may be useful for the differentiation between CBD and PSP.

Platelet superoxide dismutase in migraine and tension‐type headache

Superoxide dismutase (SOD) is a radical-scavenging enzyme. We determined Cu, Zn-SOD concentrations and activities in platelets from subjects with migraine and tension-type headaches. Thirty migraine without aura (MWoA) patients, 9 migraine with aura (MWA) patients, and 53 tension-type headache patients were selected for study. Thirty healthy volunteers composed the control group. Concentrations of platelet SOD were determined using enzyme-linked immunosorbent assay techniques. The activity of platelet SOD was determined by measuring reductivity of nitroblue tetrazolium. Low concentrations of platelet SOD were found in patients with MWA and MWoA. Platelet SOD activity decreased in MWA patients but not in patients with MWoA or tension-type headaches. These findings suggest vulnerability to oxidative stress in patients with migraine. It is suggested that low platelet SOD levels may play an important role in the etiology of migraine.