Moyamoya vasculopathy - Patient demographics and characteristics in the Finnish population.

Background and purpose Moyamoya vasculopathy, a rare steno-occlusive progressive cerebrovascular disorder, has not been thoroughly studied in Caucasian populations. We established a registry of Finnish patients treated at the Helsinki University Hospital, to collect and report demographic and clinical data. Methods We collected data both retrospectively and prospectively from all the patients with a moyamoya vasculopathy referred to our hospital between January 1987 and December 2014. All patients underwent a neurological outpatient clinic visit. Results We diagnosed 61 patients (50 females, 10 children) with moyamoya vasculopathy. The mean age at the disease-onset was 31.5 ± 17.9 years. The two most common presenting symptoms were ischemic stroke (n = 31) and hemorrhage (n = 8). Forty-four percent underwent revascularization surgery, and 70% were prescribed antithrombotic treatment. Conclusions The results support in part the Western phenotype of the disease considering the later presentation and larger female predominance compared to the Asian moyamoya vasculopathy reports. However, the proportion of ischemic strokes and hemorrhagic strokes is closer to Japanese population than German population. The absence of familial cases points to a different genetic profile in the Finnish patients.

[Alertness in transient visual disturbances of one eye]. / Ohimenevä toisen silmän näköhäiriö vaatii valppautta.

TIA is a brief and transient ictal symptom due to a local disturbance of cerebral or ocular arterial circulation. Transitory blindness or blurred vision in one eye (amaurosis fugax) is a sudden TIA symptom lasting a few minutes, usually underlied by thromboembolism originating from an atherosclerotic plaque of the internal carotid artery, less frequently an embolus from the aorta or the heart, or localized thrombosis of vessels of the optic nerve or the retina. We describe two amaurosis fugax patients.

Carotid embolectomy and endarterectomy for symptomatic complete occlusion of the carotid artery as a rescue therapy in acute ischemic stroke.

Emergency endarterectomy of an occluded internal carotid artery (ICA) has not been investigated as an option of rescue therapy for severe acute ischemic stroke in the era of intravenous (IV) thrombolysis treatment neither as a primary treatment nor after failed IV thrombolysis. Data from the pre-IV thrombolysis era are conflicting and therefore emergency endarterectomy has not been recommended. The number of patients reaching the emergency room within the IV thrombolysis time window has vastly grown due to advanced acute stroke treatment protocols. The efficacy of mechanical thrombectomy as a primary or add-on to IV thrombolysis therapy option is being actively investigated. We herein report 2 cases of acute ischemic stroke with computerized tomography (CT) angiography-documented occlusion of an ICA that were treated with emergency carotid endarterectomy and embolectomy to restore cerebral blood flow. Both cases presented with severe stroke symptoms and signs not responding to IV thrombolysis and showed severe CT-perfusion deficits mainly representing ischemic penumbra. Blood flow was surgically restored after 5 h of symptom onset. Both patients achieved a favorable outcome. We conclude that timely surgical approach of acute ICA occlusion after failed thrombolysis as a rescue therapy may be a viable option in well-selected patients.

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia.

Interleukin-1beta (IL-1beta) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1beta gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53-41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (chi(2) = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 +/- 7.7 and 22.7 +/- 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.

Osteopontin levels are associated with cholesterol synthesis markers in mildly hypercholesterolaemic patients.

OBJECTIVE: Atherosclerotic lesions are characterized by an accumulation of inflammatory cells and lipids. Osteopontin (OPN) is a cell-binding phosphoprotein, and it seems to promote the development of atherosclerosis. The purpose of our study was to find out whether plasma levels of OPN are associated with cholesterol metabolites in plasma or tissues. METHODS AND RESULTS: Forty-three normal or mildly hypercholesterolaemic subjects, aged 31 to 69, were studied. The plasma level of OPN correlated negatively with muscle lathosterol (r = -0.52, P < 0.0001) and with the muscle lathosterol to muscle cholesterol ratio (r = -0.48, P = 0.001). Lathosterol concentrations in muscle (P = 0.003) and in relation to cholesterol (P = 0.005) were also significantly different among the OPN tertiles. OPN correlated negatively and significantly with muscle lathosterol in men (r = -0.58, P = 0.001, n = 29) but not in women (r = -0.21, P = 0.48, n = 14). Correspondingly, it also correlated negatively and significantly with the muscle lathosterol to muscle cholesterol ratio (r = -0.60, P = 0.001) in men but not in women (r = -0.13, P = 0.65). Plasma levels of OPN had a non-significant inverse correlation with plasma lathosterol and the plasma lathosterol to plasma cholesterol ratio. Plasma OPN concentrations were not related to plant sterols, cholesterol and 27-hydroxycholesterol. CONCLUSIONS: Tissue markers of cholesterol synthesis were related to plasma OPN, particularly in men. This suggests that there is interplay between OPN and cholesterol metabolism in human cells.

Plasma asymmetric dimethylarginine (ADMA), nitrate and the indices of low-density lipoprotein oxidation.

BACKGROUND: Oxidative modification of low-density lipoprotein (LDL) is an important contributor to atherosclerosis. Also, oxidized LDL is suspected to cause accumulation of asymmetric dimethylarginine (ADMA), an endogenous competitive nitric oxide synthase inhibitor, which is suggested to be an independent risk factor for atherosclerosis. This study was performed to evaluate how plasma ADMA is related to plasma nitric oxide production, oxidized LDL and ex vivo susceptibility of LDL to oxidation in mildly hypercholesterolemic otherwise healthy subjects. METHODS: Plasma ADMA was determined using high performance liquid chromatography tandem mass spectrometry. LDL oxidation was estimated by the lag time and rate of copper-induced LDL oxidation. The nitric oxide production in plasma was estimated based on nitrate (NO(3)(-)) determination and plasma oxidized LDL was determined by a capture ELISA. RESULTS: Low ADMA was a significant determinant for high LDL oxidation rate and concentration of plasma ADMA was associated with nitrate levels. CONCLUSIONS: There may be an interplay between LDL fatty acid oxidation rate and plasma ADMA and nitrate. We hypothesize that plasma ADMA has a bivalent role: high ADMA may have a protective role in decelerating LDL fatty acid oxidation and also a risk factor for endothelial dysfunction by decreasing availability of nitric oxide.

No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer's or Parkinson's disease.

The brain-derived neurotrophic factor (BDNF) promotes survival, differentiation and maintenance of neurons in the central nervous system. BDNF 196 G>A and 270 C>T polymorphisms have previously been associated with Alzheimer's disease (AD) and with Parkinson's disease (PD). To study the role of BDNF 196 G>A and 270 C>T polymorphisms in Finnish AD and PD patients we genotyped BDNF 196 G>A and 270 C>T polymorphisms in 97 sporadic AD patients, 52 PD patients and 101 control subjects with polymerase chain reaction. No associations were found between the genotypes studied and AD or PD in Finnish patients. Moreover, no interaction between either BDNF polymorphism and the epsilon 4 allele of apolipoprotein E was found. In conclusion, it seems that the BDNF gene does not contribute significantly to the risk of AD or PD in Finnish patients.

Neuregulin genotype and medication response in Finnish patients with schizophrenia.

Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia.

Interaction between matrix metalloproteinase 3 and the epsilon4 allele of apolipoprotein E increases the risk of Alzheimer's disease in Finns.

Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position -1607 (1G/2G) in MMP1 and at -1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer's disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson's disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE 4 alleles (P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8-144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE 4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE 4, may contribute to the development of AD.

Effect of long-term hormone replacement therapy on atherosclerosis progression in postmenopausal women relates to myeloperoxidase promoter polymorphism.

Myeloperoxidase (MPO) is an oxidative enzyme present in phagocytes and atherosclerotic lesions. The MPO gene has a promoter polymorphism -463G/A, which leads to high (GG) and low expression (AG, AA) genotypes. We investigated the effect of long-term hormone replacement therapy (HRT) on the progression of atherosclerosis in a 5-yr follow-up study of postmenopausal women with different MPO genotypes. Eighty-seven nonsmoking postmenopausal women, aged 45-71 yr, were divided into three groups based on the use of HRT. The HRT-EVP group (n = 25) used sequential estradiol valerate plus progestin, the HRT-EV group used estradiol valerate alone (n = 32), and the control group (n = 30) used no HRT. The atherosclerosis severity score (ASC) for abdominal aorta and carotid arteries was determined by ultrasonography, and the MPO genotype was analyzed. In subjects with the GG genotype, the progression of ASC was significantly faster in the control group than in the HRT group (genotype by time interaction, P = 0.042), whereas in A allele carriers there were no significant differences in ASC progression between control and HRT. The effects of HRT on atherosclerosis progression in subjects with the GG genotype seem to be especially beneficial compared with controls with the same genotype but without HRT. These results may help us understand in greater detail the benefit and possible risk of HRT in atherosclerotic diseases.

Differential intracellular expression of CCR5 and chemokines in multiple sclerosis subtypes.

Chemokines are small chemoattractant cytokines which participate in the migration of immune cells into the CNS and contribute to the T cell-mediated pathogenesis of multiple sclerosis (MS). The expression of chemokines and their receptors in freshly isolated mononuclear cells from peripheral blood (PBMC) was studied in relation to MS subtype, disease duration and progression in a total of 57 patients with MS (22 relapsing remitting, RRMS; 21 secondary progressive, SPMS; 14 primary progressive, PPMS) and 17 healthy controls. The RNA expression of CCR5 in PBMC was analysed by reverse transcription polymerase chain reaction (RT-PCR) using specific oligonucleotide primers. The PBMC levels of CCR5-ligands MIP-1 alpha/beta and RANTES, and chemokines MCP-1, IL-8, lymphotactin, IP-10 and I-309 were analysed by ribonuclease protection assay (RPA). Significantly increased intracellular CCR5 RNA expression intensity was detected in PPMS when compared with SPMS ( p=0.009), RRMS ( p=0.013), and controls ( p=0.023). However, the surface expression of CCR5 on CD4(+) cells from PBMC, analysed by flow cytometry, appeared to be similar in all MS subtypes and controls. The CCR5-ligands RANTES and MIP-1b were expressed constitutively in all patients and controls. Interleukin-8 was found in all MS subtypes and controls, but IP-10 was detected only in RRMS and SPMS, and lymphotactin occasionally in other subtypes but PPMS. MCP-1, MIP-1a or I-309 were not expressed in any of the groups studied. A correlation was found between the RNA levels of RANTES and CCR5 in PPMS ( r=0.735). Differential profile in the expression of CCR5 and chemokines between PPMS and other MS subtypes may contribute to differences in the pathogenesis of MS and thus can be of importance in the development of new treatments for MS.