Mitja Kurki - Academia.edu (original) (raw)

Papers by Mitja Kurki

Epilepsia, Jan 15, 2015

Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported ... more Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with ...

PLoS Genetics, 2014

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a spo... more 3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is .26 increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p,5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants.

Neurosurgery, 2011

Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a... more Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease. To investigate gene expression patterns distinguishing ruptured and unruptured sIA. We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes. Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes. We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.

Neurosurgery, Oct 3, 2012

Background: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be ... more Background: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce.

Neurobiology of Disease, 2015

Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying ... more Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer's disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co-cultures under neuroinflammation. Taken together, these results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation.

Journal of Alzheimer's Disease, 2015

Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer&a... more Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ-secretase activity. Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. The genome-wide expression profile of ∼35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα, sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. After correcting the results for multiple testing, significant differences in the expression of TTR and A β PP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A β PP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of α-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAβPPα and sAβPPβ, but TTR levels did not predict the brain pathology or the shunt response. These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients.

Journal of Alzheimer's disease : JAD, Jan 22, 2015

Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's... more Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ-secretase activity. Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. The genome-wide expression profile of ∼35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα, sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. After correcting the results for multiple testing, significant differences in the express...

Fluids and Barriers of the CNS, 2015

Neurology, Jan 6, 2015

The aim was to elucidate the incidence and risk factors of epilepsy after subarachnoid hemorrhage... more The aim was to elucidate the incidence and risk factors of epilepsy after subarachnoid hemorrhage (SAH) from saccular intracranial aneurysm (sIA) in a population-based cohort. The Kuopio sIA Database (www.uef.fi/ns) includes all unruptured and ruptured sIA cases admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland. The use of prescribed medicines, including reimbursable antiepileptic drugs, has been entered from the Finnish national registries. The cumulative incidence and independent risk factors of epilepsy and death were analyzed in 876 patients with sIA-SAH admitted from 1995 to 2007. The competing risks analysis was used to correctly estimate the probability of epilepsy, because epilepsy and death after sIA-SAH may share risk factors. The follow-up ended at death (n = 200) or December 31, 2008; median follow-up time was 76 months. Epilepsy was diagnosed in 113 patients in a median of 8 months after sIA-SAH. Cumulative incidence of ...

Journal of Alzheimer's disease : JAD, 2015

Several risk loci for Alzheimer's disease (AD) have been identified during recent years in la... more Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. To investigate the individual and combined risk effects of the newly identified AD loci. Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in t...

World neurosurgery, 2012

Delayed ischemic neurologic deficit (DIND) is a serious complication of acute aneurysmal subarach... more Delayed ischemic neurologic deficit (DIND) is a serious complication of acute aneurysmal subarachnoid hemorrhage (aSAH). Although oral nimodipine is accepted as standard care for the prevention of DIND, the intravenous route is preferred by several centers. In the present study we compared the clinical efficacy between enteral and intravenous nimodipine after aSAH. A total of 171 aSAH patients were randomly assigned to either the enteral (84 patients) or the intravenous (87 patients) nimodipine group and were compared regarding the incidence of DIND, number of new ischemic lesions on 12-month brain magnetic resonance image, and clinical outcome 12 months after aSAH as assessed by Glasgow Outcome scale, modified Rankin scale, and Karnofsky scale. Health-related quality of life was also assessed by the 15D questionnaire 12 months after aSAH. The incidence of DIND did not differ significantly between the groups (20% in the enteral versus 16% in the intravenous group, P=0.61), whereas n...

Neurosurgery, 2013

Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated b... more Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidenc...

Neurology, 2014

We investigated whether risk alleles of single nucleotide polymorphisms associated with intracran... more We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size-weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10(-4)), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10(-5)). GRS were not...

Neurobiology of Aging, 2015

In this study, we have assessed the expression and splicing status of genes involved in the patho... more In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-β positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-β-secretase interaction, increased amyloid-β40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.

Annals of Medicine, 2014

Hypertension associates with subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH... more Hypertension associates with subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) when compared to matched controls or general population. Few series compare hypertension in unruptured sIA versus sIA-SAH, so its impact on the sIA disease remains uncertain. Kuopio sIA Database ( www.uef.fi/ns ) contains all cases of unruptured and ruptured sIAs admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We compared the age-adjusted incidence of drug-treated hypertension in 467 unruptured and 1053 ruptured sIA patients admitted to Kuopio University Hospital from 1995 to 2007, using the national registry of prescribed medicines. Antihypertensive medication was more frequent in the unruptured (73% versus 62%) with higher age-adjusted incidence. At sIA diagnosis, the sIA-SAH group had more often untreated hypertension (29% versus 23%). The size of unruptured sIAs increased with age at sIA diagnosis, independently of hypertension. Multiple sIAs, familial sIA, and sIA-SAH were not associated with hypertension in multivariate analysis. Results indicate that drug-treated hypertension associates with the formation of sIAs rather than their growth or rupture. Hypertension is highly prevalent in the carriers of unruptured sIAs when compared to those with ruptured sIA. Hypertension may associate with the sIA formation, and may predispose to the rupture of sIA if untreated.

PLoS Genetics, 2012

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, t... more Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n FIN = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p FIN = 3.01E-05, p ICBP-GWAS = 0.0007, p ALL = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.

World Neurosurgery, 2012

To analyze the impact of factors known after admission on mortality attributable to aneurysmal su... more To analyze the impact of factors known after admission on mortality attributable to aneurysmal subarachnoid hemorrhage (SAH) resulting from saccular intracranial aneurysm (IA). Data of 1657 consecutive patients admitted alive within 24 hours after aneurysmal SAH to Kuopio Neurosurgery during the years 1980-2007 from a defined population were analyzed. Aneurysmal SAH caused excess mortality for 12 months, after which other causes of death became dominant. The 12-month mortality curve on a logarithmic time scale indicated acute (first 3 days), subacute (4-30 days), and delayed (1-12 months) mortality, with cumulative rates of 11% at 3 days, 22% at 30 days, and 27% at 12 months. The acute mortality was predicted by Hunt & Hess (H&H) grades IV-V, ruptured aneurysm ≥ 15 mm, and acute subdural hematoma. Age, gender, intracerebral hemorrhage (ICH), and time period of admission were not independent risk factors. Advanced age, H&H grades IV-V, intraventricular hemorrhage (IVH), giant ruptured saccular IA, ruptured saccular IA on the internal carotid artery or the basilar artery bifurcation, and severe hydrocephalus in different combinations predicted subacute and delayed mortality. Patients in good condition on admission had a mortality rate of only 3.5% at 12 months, regardless of age. Sequelae of aneurysmal SAH were the leading cause of death for 12 months. Mortality analysis of this period displayed three phases with distinct independent risk factors. These data support the creation of prognosticators for prediction on admission of the everyday individual risk of death until 12 months after aneurysmal SAH.

PLoS Genetics, 2014

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a spo... more 3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is .26 increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p,5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants.

Epilepsia, Jan 15, 2015

Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported ... more Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with ...

PLoS Genetics, 2014

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a spo... more 3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is .26 increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p,5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants.

Neurosurgery, 2011

Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a... more Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease. To investigate gene expression patterns distinguishing ruptured and unruptured sIA. We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes. Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes. We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.

Neurosurgery, Oct 3, 2012

Background: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be ... more Background: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce.

Neurobiology of Disease, 2015

Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying ... more Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer's disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co-cultures under neuroinflammation. Taken together, these results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation.

Journal of Alzheimer's Disease, 2015

Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer&a... more Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ-secretase activity. Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. The genome-wide expression profile of ∼35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα, sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. After correcting the results for multiple testing, significant differences in the expression of TTR and A β PP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A β PP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of α-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAβPPα and sAβPPβ, but TTR levels did not predict the brain pathology or the shunt response. These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients.

Journal of Alzheimer's disease : JAD, Jan 22, 2015

Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's... more Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ-secretase activity. Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. The genome-wide expression profile of ∼35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα, sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. After correcting the results for multiple testing, significant differences in the express...

Fluids and Barriers of the CNS, 2015

Neurology, Jan 6, 2015

The aim was to elucidate the incidence and risk factors of epilepsy after subarachnoid hemorrhage... more The aim was to elucidate the incidence and risk factors of epilepsy after subarachnoid hemorrhage (SAH) from saccular intracranial aneurysm (sIA) in a population-based cohort. The Kuopio sIA Database (www.uef.fi/ns) includes all unruptured and ruptured sIA cases admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland. The use of prescribed medicines, including reimbursable antiepileptic drugs, has been entered from the Finnish national registries. The cumulative incidence and independent risk factors of epilepsy and death were analyzed in 876 patients with sIA-SAH admitted from 1995 to 2007. The competing risks analysis was used to correctly estimate the probability of epilepsy, because epilepsy and death after sIA-SAH may share risk factors. The follow-up ended at death (n = 200) or December 31, 2008; median follow-up time was 76 months. Epilepsy was diagnosed in 113 patients in a median of 8 months after sIA-SAH. Cumulative incidence of ...

Journal of Alzheimer's disease : JAD, 2015

Several risk loci for Alzheimer's disease (AD) have been identified during recent years in la... more Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. To investigate the individual and combined risk effects of the newly identified AD loci. Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in t...

World neurosurgery, 2012

Delayed ischemic neurologic deficit (DIND) is a serious complication of acute aneurysmal subarach... more Delayed ischemic neurologic deficit (DIND) is a serious complication of acute aneurysmal subarachnoid hemorrhage (aSAH). Although oral nimodipine is accepted as standard care for the prevention of DIND, the intravenous route is preferred by several centers. In the present study we compared the clinical efficacy between enteral and intravenous nimodipine after aSAH. A total of 171 aSAH patients were randomly assigned to either the enteral (84 patients) or the intravenous (87 patients) nimodipine group and were compared regarding the incidence of DIND, number of new ischemic lesions on 12-month brain magnetic resonance image, and clinical outcome 12 months after aSAH as assessed by Glasgow Outcome scale, modified Rankin scale, and Karnofsky scale. Health-related quality of life was also assessed by the 15D questionnaire 12 months after aSAH. The incidence of DIND did not differ significantly between the groups (20% in the enteral versus 16% in the intravenous group, P=0.61), whereas n...

Neurosurgery, 2013

Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated b... more Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidenc...

Neurology, 2014

We investigated whether risk alleles of single nucleotide polymorphisms associated with intracran... more We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size-weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10(-4)), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10(-5)). GRS were not...

Neurobiology of Aging, 2015

In this study, we have assessed the expression and splicing status of genes involved in the patho... more In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-β positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-β-secretase interaction, increased amyloid-β40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.

Annals of Medicine, 2014

Hypertension associates with subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH... more Hypertension associates with subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) when compared to matched controls or general population. Few series compare hypertension in unruptured sIA versus sIA-SAH, so its impact on the sIA disease remains uncertain. Kuopio sIA Database ( www.uef.fi/ns ) contains all cases of unruptured and ruptured sIAs admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We compared the age-adjusted incidence of drug-treated hypertension in 467 unruptured and 1053 ruptured sIA patients admitted to Kuopio University Hospital from 1995 to 2007, using the national registry of prescribed medicines. Antihypertensive medication was more frequent in the unruptured (73% versus 62%) with higher age-adjusted incidence. At sIA diagnosis, the sIA-SAH group had more often untreated hypertension (29% versus 23%). The size of unruptured sIAs increased with age at sIA diagnosis, independently of hypertension. Multiple sIAs, familial sIA, and sIA-SAH were not associated with hypertension in multivariate analysis. Results indicate that drug-treated hypertension associates with the formation of sIAs rather than their growth or rupture. Hypertension is highly prevalent in the carriers of unruptured sIAs when compared to those with ruptured sIA. Hypertension may associate with the sIA formation, and may predispose to the rupture of sIA if untreated.

PLoS Genetics, 2012

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, t... more Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n FIN = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p FIN = 3.01E-05, p ICBP-GWAS = 0.0007, p ALL = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.

World Neurosurgery, 2012

To analyze the impact of factors known after admission on mortality attributable to aneurysmal su... more To analyze the impact of factors known after admission on mortality attributable to aneurysmal subarachnoid hemorrhage (SAH) resulting from saccular intracranial aneurysm (IA). Data of 1657 consecutive patients admitted alive within 24 hours after aneurysmal SAH to Kuopio Neurosurgery during the years 1980-2007 from a defined population were analyzed. Aneurysmal SAH caused excess mortality for 12 months, after which other causes of death became dominant. The 12-month mortality curve on a logarithmic time scale indicated acute (first 3 days), subacute (4-30 days), and delayed (1-12 months) mortality, with cumulative rates of 11% at 3 days, 22% at 30 days, and 27% at 12 months. The acute mortality was predicted by Hunt & Hess (H&H) grades IV-V, ruptured aneurysm ≥ 15 mm, and acute subdural hematoma. Age, gender, intracerebral hemorrhage (ICH), and time period of admission were not independent risk factors. Advanced age, H&H grades IV-V, intraventricular hemorrhage (IVH), giant ruptured saccular IA, ruptured saccular IA on the internal carotid artery or the basilar artery bifurcation, and severe hydrocephalus in different combinations predicted subacute and delayed mortality. Patients in good condition on admission had a mortality rate of only 3.5% at 12 months, regardless of age. Sequelae of aneurysmal SAH were the leading cause of death for 12 months. Mortality analysis of this period displayed three phases with distinct independent risk factors. These data support the creation of prognosticators for prediction on admission of the everyday individual risk of death until 12 months after aneurysmal SAH.

PLoS Genetics, 2014

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a spo... more 3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is .26 increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p,5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants.