Publications by authors named "Pauli Ylikotila"

11 Publications

  • Page 1 of 1

Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults.

Ann Neurol 2021 02 12;89(2):242-253. Epub 2020 Nov 12.

Neurology, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.

Objective: To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).

Methods: We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (±5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen.

Results: The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO.

Interpretation: MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2021;89:242-253.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25937DOI Listing
February 2021

Finnish Parkinson's disease study integrating protein-protein interaction network data with exome sequencing analysis.

Sci Rep 2019 12 11;9(1):18865. Epub 2019 Dec 11.

Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland.

Variants associated with Parkinson's disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4-5.2; p < 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-55479-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906405PMC
December 2019

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate-induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy.

Epilepsia 2018 11 26;59(11):2125-2136. Epub 2018 Sep 26.

Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology, University of Oulu, Oulu, Finland.

Objective: Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA-induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy.

Methods: Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected.

Results: A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion.

Significance: POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.14568DOI Listing
November 2018

Genetic risk factors in Finnish patients with Parkinson's disease.

Parkinsonism Relat Disord 2017 Dec 29;45:39-43. Epub 2017 Sep 29.

Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland; Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. Electronic address:

Introduction: Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population.

Methods: The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES).

Results: We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients.

Conclusions: The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2017.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812481PMC
December 2017

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

Eur Stroke J 2017 Jun 4;2(2):116-125. Epub 2017 Apr 4.

Division of Neurology and Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Canada.

Background: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies.

Key Hypotheses/aims: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions.

Design: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case-control study enrolling patients aged 18-49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient-control pairs enrolled by the end of 2018.

Summary: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2396987317703210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453214PMC
June 2017

Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study.

Neurobiol Aging 2017 05 2;53:195.e7-195.e10. Epub 2017 Feb 2.

Research Unit of Clinical Neuroscience, Department of Neurology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Department of Neurology, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Neurology, Oulu University Hospital, Oulu, Finland.

Several genes and risk factors are associated with Parkinson's disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been found. Here, we carried out whole-exome sequencing (WES) on 438 Finnish patients with early-onset PD. We also reanalyzed previous data from genome-wide association studies (GWAS) on the same cohort. Variants in the CEL gene/locus were associated with PD in both GWAS and WES analysis. Exome-wide gene-based association tests also identified the MPHOSPH10, TAS2R19, and SERPINA1 genes in the discovery data set (p < 2.5E-6). MPHOSPH10 had estimated odds ratio (OR) of 1.53, and the rs141620200 variant in SERPINA1 had OR of 1.27. We identified several candidate genes, but further investigation is required to determine the role of these genes in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2017.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385296PMC
May 2017

Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy.

Reprod Toxicol 2015 Nov 14;57:204-6. Epub 2015 Jul 14.

Institute of Clinical Medicine, Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland; Medbase Ltd., Turku, Finland. Electronic address:

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke, accounting to less than 1% of all strokes. We describe a pregnant woman with a massive CVT in early pregnancy, complicated by status epilepticus. The mother was treated with levetiracetam, lacosamide, and enoxaparin throughout pregnancy. A male infant was born on pregnancy week 36, weighing 2.2kg. Both levetiracetam and and lacosamide were present in cord blood in levels similar to those in maternal blood. The infant was partially breast-fed and experienced poor feeding and sleepiness, starting to resolve after two first weeks. Milk samples were drawn 5 days after the delivery and a blood sample from the infant 3 days later. Lacosamide level in milk was low, resulting in an estimated relative infant dose of 1.8% of the maternal weight-adjusted daily dose in a fully breast-fed infant. This is the first case describing lacosamide use during pregnancy and lactation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.reprotox.2015.07.068DOI Listing
November 2015

Epidemiology of early-onset Parkinson's disease in Finland.

Parkinsonism Relat Disord 2015 Aug 4;21(8):938-42. Epub 2015 Jun 4.

Division of Clinical Neurosciences, Neurology, University of Oulu, Oulu, Finland; Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. Electronic address:

Objective: The contribution of genetic causes to Parkinson's disease (PD) is strongest in early-onset cases. We ascertained a nationwide cohort of patients in order to study the genetic epidemiology of early-onset PD (EOPD) in Finland.

Methods: By means of a search in a national database we ascertained all patients with EOPD. These patients had become eligible for reimbursement of PD drugs between the years 1995-2006 and were <55 years of age at the time of PD diagnosis. A total of 441 patients consented and provided clinical and genealogical information.

Results: The incidence of EOPD increased 1.7-fold between the years 1995-2006, the mean annual incidence being 3.3/100,000. Fifty-two patients (11.8%) reported an affected first-degree relative. The birthplaces of patients with PD among first-degree relatives were clustered in certain regions in the southwestern and western coastal provinces of Finland and in the eastern province of Savo. Furthermore, the distance between the birthplaces of the patients' parents was smaller for patients, who had first-degree relatives with PD than for patients with no family history of PD.

Conclusions: Our data suggest that the incidence of EOPD is increasing. The birthplaces of patients with PD among first-degree relatives were clustered in certain provinces of Finland suggesting that monogenic forms of PD or genetic susceptibility of PD are present in the population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2015.06.003DOI Listing
August 2015

Genome wide assessment of young onset Parkinson's disease from Finland.

PLoS One 2012 24;7(7):e41859. Epub 2012 Jul 24.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.

In the current study we undertook a series of experiments to test the hypothesis that a monogenic cause of disease may be detectable within a cohort of Finnish young onset Parkinson's disease patients. In the first instance we performed standard genome wide association analyses, and subsequent risk profile analysis. In addition we performed a series of analyses that involved testing measures of global relatedness within the cases compared to controls, searching for excess homozygosity in the cases, and examining the cases for signs of excess local genomic relatedness using a sliding window approach. This work suggested that the previously identified common, low risk alleles, and the risk models associated with these alleles, were generalizable to the Finnish Parkinson's disease population. However, we found no evidence that would suggest a single common high penetrance mutation exists in this cohort of young onset patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404082PMC
February 2013

Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.

Hum Mol Genet 2012 Nov 13;21(22):4996-5009. Epub 2012 Aug 13.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/dds335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576713PMC
November 2012

[Use of CSF biomarkers in the diagnostics of memory diseases].

Duodecim 2009 ;125(20):2215-22

Oulun yliopisto, neurologian klinikka.

Alzheimer's disease is the most common cause of dementia. Early diagnosis of diseases leading to dementia is cost-effective. However, early diagnosis of Alzheimer's disease may be difficult and should not be based on exclusion of other reasons for dementia. A decreased CSF amyloid beta-peptide-42 level together with elevated tau or phosphorylated tau levels can differentiate patients with AD from control subjects or patients with other neurologic conditions with relatively high accuracy. We evaluated the use of these biomarkers in 452 patient cohort during 2005-2007 in clinical practice. Cerebrospinal fluid biomarkers seem to be useful especially to confirm Alzheimer's disease diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2010