Publications by authors named "Laura L Kilarski"

10 Publications

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Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis.

Eur Neuropsychopharmacol 2017 11 5;27(11):1090-1109. Epub 2017 Oct 5.

Charité Universitätsmedizin Berlin, Campus Mitte, Department for Psychiatry and Psychotherapy, Charitéplatz 1, 10117 Berlin, Germany. Electronic address:

In this article, we aimed to assess the efficacy of adjunctive administration of nutritional supplements to antidepressants by means of a systematic review and meta-analysis. The supplements included were inositol, vitamin D, folic acid, vitamin B12, S-adenosyl-L-methionine (SAMe), omega-3 polyunsaturated fatty acids (n-3 PUFA) and zinc. A structured database search (MEDLINE, EBSCO, CENTRAL, Web of Science) was performed using terms for the respective substances in conjunction with terms for depression and the mode of treatment ("add-on" OR "adjunctive" OR "augmentation"). Meta-analyses, randomized controlled trials (RCTs) and non-randomized comparative studies that investigated the supplements as an add-on in the treatment of clinically diagnosed MDD were included. Agents had to be added to an existing antidepressant regime (augmentation) or started simultaneously with the antidepressant (acceleration). For n-3 PUFAs, folic acid and zinc, new meta-analyses were performed as part of this work. Our meta-analyses of 10 articles on n-3 PUFAs and four on zinc support their efficacy. For folic acid, our meta-analysis does not support efficacy. For n-3 PUFAs, sensitivity analysis showed no difference between acceleration and augmentation designs, but significant differences between individuals with or without comorbidities. For the remaining substances, only a few RCTs were available. The preliminary data on inositol was negative, while one RCT for vitamin D demonstrated positive results. For vitamin B12 one and for SAMe two RCTs and a few open trials are available reporting positive and mixed results. To summarize, for most of the substances, the available data is not yet sufficient or inconclusive.
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http://dx.doi.org/10.1016/j.euroneuro.2017.07.004DOI Listing
November 2017

Efficacy of off-label augmentation in unipolar depression: A systematic review of the evidence.

Eur Neuropsychopharmacol 2017 05 17;27(5):423-441. Epub 2017 Mar 17.

Charité, Department of Psychiatry and Psychotherapy, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. Electronic address:

Treatment of unipolar depression with currently available antidepressants is still unsatisfactory. Augmentation with lithium or second generation antipsychotics is an established practice in non-responders to antidepressant monotherapy, but is also associated with a substantial non-response rate and with non-tolerance. Based on a systematic review of the literature, including meta-analyses, randomized controlled trials (RCTs), non-randomized comparative studies and case studies, off-label augmentation agents (administered in addition to an antidepressant, without FDA approval for treatment of MDD) were identified and evaluated regarding their efficacy using levels of evidence. The agents had to be added to an existing antidepressant regime with the aim of achieving an improved clinical response to an ongoing antidepressant treatment (augmentation) or an earlier onset of effect when starting antidepressant and augmentation agent simultaneously (acceleration). Five substances, modafinil, ketamine, pindolol, testosterone and estrogen (the latter two in hormone-deficient patients) were shown to be clinically effective in high evidence studies. For the six drugs dexamethasone, mecamylamine, riluzole, amantadine, pramipexole and yohimbine clear proof of efficacy was not possible due to low levels of evidence, small sample sizes or discordant results. For the two agents methylphenidate and memantine only studies with negative outcomes could be found. Overall, the quality of study designs was low and results were often contradictory. However, the use of pindolol, ketamine, modafinil, estrogen and testosterone might be an option for depressed patients who are not responding to antidepressant monotherapy or established augmentation strategies. Further high quality studies are necessary and warranted.
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http://dx.doi.org/10.1016/j.euroneuro.2017.03.003DOI Listing
May 2017

Are antidepressants effective? A debate on their efficacy for the treatment of major depression in adults.

Expert Rev Neurother 2016 17;16(4):367-74. Epub 2016 Mar 17.

c Faculty of Medicine , University of Cologne , Köln , Germany.

Recently, the efficacy of antidepressants, a treatment used by 11% of US American adults, has been debated. Thousands of randomized controlled trials (RCTs) have been used to study antidepressants, with the majority demonstrating at least moderate superiority over placebo. In contrast, studies have found antidepressant effects to be unspecific and mainly resulting from placebo. The effects of antidepressants may also be overestimated due to selective publishing and selection of patients who have a high chance of response in RCTs. Studies have also shown the drugs do not reduce suicidal events when compared to placebo, and efficacy differences to placebo are often too small to prove clinical relevance. Here, we review the claims for and against antidepressant efficacy.
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http://dx.doi.org/10.1586/14737175.2016.1155985DOI Listing
December 2016

Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke.

PLoS One 2015 25;10(8):e0136352. Epub 2015 Aug 25.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Background And Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct.

Methods: Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI's and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations.

Results: Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD.

Conclusion: CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549151PMC
May 2016

Differential effects of severe vs mild GBA mutations on Parkinson disease.

Neurology 2015 Mar 4;84(9):880-7. Epub 2015 Feb 4.

From The Genetic Institute (Z.G.-O., I.A., A.B.-S., M.G.-W., A.O.-R.) and Movement Disorders Unit, Parkinson Center, and Department of Neurology (A.M., N.G.), Tel Aviv Sourasky Medical Center; The Sackler Faculty of Medicine (N.G., A.O.-U.), Tel Aviv University, Israel; Stroke and Dementia Research Centre (L.L.K.), St. George's, University of London, UK; Columbia University (K.M.), Columbia Presbyterian Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY. Z.G.-O. is currently affiliated with the Department of Human Genetics and Montreal Neurological Institute, McGill University, Montreal, Canada.

Objective: To better define the genotype-phenotype correlations between the type of GBA (glucosidase, beta, acid) mutation, severe or mild, and the risk and age at onset (AAO), and potential mechanism of Parkinson disease (PD).

Methods: We analyzed 1,000 patients of Ashkenazi-Jewish descent with PD for 7 founder GBA mutations, and conducted a meta-analysis of risk and AAO according to GBA genotype (severe or mild mutation). The meta-analysis included 11,453 patients with PD and 14,565 controls from worldwide populations. The statistical analysis was done with and without continuity correction (constant or empirical), considering biases that could potentially affect the results.

Results: Among Ashkenazi-Jewish patients with PD, the odds ratios for PD were 2.2 and 10.3 for mild and severe GBA mutation carriers, respectively. The observed frequency of severe GBA mutation carriers among patients with PD was more than 4-fold than expected (4.4% vs 0.9%, respectively, p < 0.0001, Fisher exact test). In the different models of the meta-analysis, the odds ratios for PD ranged between 2.84 and 4.94 for mild GBA mutation carriers and 9.92 and 21.29 for severe GBA mutation carriers (p < 1 × 10(-6) for all analyses). Pooled analysis demonstrated AAO of 53.1 (±11.2) and 58.1 (±10.6) years for severe and mild GBA mutation carriers, respectively (p = 4.3 × 10(-5)).

Conclusions: These data demonstrate that mild and severe heterozygous GBA mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.
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http://dx.doi.org/10.1212/WNL.0000000000001315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351661PMC
March 2015

A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach.

PLoS Genet 2014 Jul 31;10(7):e1004469. Epub 2014 Jul 31.

Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Center for Non-Communicable Diseases, Karachi, Pakistan.

Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
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http://dx.doi.org/10.1371/journal.pgen.1004469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117446PMC
July 2014

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.

Neurology 2014 Aug 16;83(8):678-85. Epub 2014 Jul 16.

Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
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http://dx.doi.org/10.1212/WNL.0000000000000707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150131PMC
August 2014

Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease.

Mov Disord 2012 Oct 6;27(12):1522-9. Epub 2012 Sep 6.

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity.
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http://dx.doi.org/10.1002/mds.25132DOI Listing
October 2012

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

Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease.

PLoS One 2012 12;7(3):e28787. Epub 2012 Mar 12.

Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.

Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity.We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort.There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028787PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299635PMC
August 2012