Publications by authors named "Marisa Loitfelder"

14 Publications

  • Page 1 of 1

Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunction, and autistic mannerisms.

J Neurodev Disord 2015 15;7:32. Epub 2015 Oct 15.

Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands.

Background: Neurofibromatosis type 1 (NF1) is a single-gene neurodevelopmental disorder, in which social and cognitive problems are highly prevalent. Several commonly observed central nervous system (CNS) abnormalities in NF1 might underlie these social and cognitive problems. Cerebral volumetric abnormalities are among the most consistently observed CNS abnormalities in NF1. This study investigated whether differences were present between NF1 patients and healthy controls (HC) in volumetric measures of cortical and subcortical brain regions and whether differential associations existed for NF1 patients and HC between the volumetric measures and parent ratings of social skills, attention problems, social problems, autistic mannerisms, and executive dysfunction.

Methods: Fifteen NF1 patients (mean age 12.9 years, SD 2.6) and 18 healthy controls (HC, mean age 13.8 years, SD 3.6) underwent 3 T MRI scanning. Segmentation of cortical gray and white matter, as well as volumetry of subcortical nuclei, was carried out. Voxel-based morphometry was performed to assess cortical gray matter density. Correlations were calculated, for NF1-patients and HC separately, between MRI parameters and scores on selected dimensions of the following behavior rating scales: the Social Skills Rating System, the Child Behavior Checklist, the Social Responsiveness Scale, the Behavior Rating Inventory of Executive Functioning, and the Dysexecutive Questionnaire.

Results: After correction for age, sex, and intracranial volume, larger volumes of all subcortical regions were found in NF1 patients compared to controls. Patients further showed decreased gray matter density in midline regions of the frontal and parietal lobes and larger total white matter volume. Significantly more social and attention problems, more autistic mannerisms, and poorer executive functioning were reported for NF1 patients compared to HC. In NF1 patients, larger left putamen volume and larger total white matter volume were associated with more social problems and poorer executive functioning, larger right amygdala volume with poorer executive functioning and autistic mannerisms, and smaller precentral gyrus gray matter density was associated with more social problems. In controls, only significant negative correlations were observed: larger volumes (and greater gray matter density) were associated with better outcomes.

Conclusions: Widespread volumetric differences between patients and controls were found in cortical and subcortical brain regions. In NF1 patients but not HC, larger volumes were associated with poorer behavior ratings.
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http://dx.doi.org/10.1186/s11689-015-9128-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607002PMC
October 2015

Longitudinal change of small-vessel disease-related brain abnormalities.

J Cereb Blood Flow Metab 2016 Jan;36(1):26-39

Knowledge about the longitudinal change of cerebral small-vessel disease–related magnetic resonance imaging abnormalities increases our pathophysiologic understanding of cerebral microangiopathy. The change of specific lesion types may also serve as secondary surrogate endpoint in clinical trials. A surrogate endpoint needs to progress fast enough to allow monitoring of treatment effects within a reasonable time period, and change of the brain abnormality needs to be correlated with clinical change. Confluent white matter lesions show fast progression and correlations with cognitive decline. Thus, the change of confluent white matter lesions may be used as a surrogate marker in proof-of-concept trials with small patient numbers needed to show treatment effects on lesion progression. Nonetheless if the expected change in cognitive performance resulting from treatment effects on lesion progression is used as outcome, the sample size needed to show small to moderate treatment effects becomes very large. Lacunes may also fulfill the prerequisites of a surrogate marker, but in the general population the incidence of lacunes over short observational periods is small. For other small-vessel disease–related brain abnormalities including microbleeds and microstructural changes in normal-appearing white matter longitudinal change and correlations with clinical decline is not yet fully determined.
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http://dx.doi.org/10.1038/jcbfm.2015.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758559PMC
January 2016

Functional Connectivity Changes and Executive and Social Problems in Neurofibromatosis Type I.

Brain Connect 2015 Jun 31;5(5):312-20. Epub 2015 Mar 31.

1 Leiden Institute for Brain and Cognition (LIBC), Leiden University , Leiden, The Netherlands .

Neurofibromatosis type 1 (NF1) has regularly been associated with cognitive, social, and behavioral problems. The fact that many different cognitive and behavioral impairments have been observed in NF1 suggests that networks of brain regions are involved rather than specific brain regions. Here, we examined whether functional connectivity was different in NF1 and, if so, whether associations were present with cognitive, social, and behavioral outcomes. Fourteen NF1 patients (8 male, age: M=12.49, SD=2.65) and 30 healthy controls (HC; 23 male, age: M=12.30, SD=2.94; p=0.835) were included. Functional connectivity was assessed using functional resting-state scanning. We analyzed brain regions that have been associated with cognitive and social functions: the bilateral ventral anterior cingulate cortex (vACC), the bilateral amygdala, the bilateral orbitofrontal cortex (OFC), and the posterior cingulate cortex (PCC). For NF1 patients, connection strengths between brain regions showing HC-NF1 differences were correlated with parent reports of cognitive, social, and behavioral functioning. Compared to HC, patients showed differences in functional connectivity between the left vACC and the frontal cortex, insula, and subcortical areas (caudate, putamen), between the left amygdala and the frontal cortex, insula, supramarginal gyrus, and PCC/precuneus, and between the left OFC and frontal and subcortical areas (caudate, pallidum). In patients, indications were found for associations between increased frontofrontal and temporofrontal functional connectivity with cognitive, social, and behavioral deficits (r-range=0.536-0.851). NF1 patients showed differences in functional connectivity between areas associated with cognitive and social functioning when compared to controls. This, plus the fact that connectivity strengths in these networks were associated with worse cognitive, social, and behavioral outcomes, suggests a neuropathological basis for the widespread deficits observed in NF1.
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http://dx.doi.org/10.1089/brain.2014.0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490703PMC
June 2015

R2* mapping for brain iron: associations with cognition in normal aging.

Neurobiol Aging 2015 Feb 19;36(2):925-32. Epub 2014 Sep 19.

Department of Neurology, Medical University of Graz, Graz, Austria. Electronic address:

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.013DOI Listing
February 2015

Functional connectivity analyses using emulated and conventional resting-state data: parts versus the whole story.

Brain Connect 2014 Dec;4(10):842-8

1 Department of Neurology, Medical University of Graz , Graz, Austria .

Continuous resting-state (RS) functional magnetic resonance imaging (fMRI) has become particularly useful to identify changes in functional connectivity (FC) in CNS disorders. Fair et al. proposed a method of volume extraction to emulate RS fMRI from block-design experiments. Whether the validity of this approach holds true in multiple sclerosis (MS) patients has not been tested formally so far. Twelve MS patients and 18 controls underwent conventional RS fMRI and a cognitive block-design fMRI. The total amount of volumes as well as the truncated set of volumes of both functional datasets was separately analyzed using a seed-based approach. Overall, seed-based analyses of FC from the anterior cingulated cortex allowed identification of the same key-network constituents using different analytical approaches, whereas higher-level within-group analyses of emulated RS versus continuous RS also revealed significant distinct differences in FC networks. Using the emulated RS approach, a general identification of connectivity networks similar to those obtained using conventional RS data also appears feasible in diseased brains. Higher-level contrasts, however, yielded different results attesting to a significant impact of employed methodology.
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http://dx.doi.org/10.1089/brain.2013.0220DOI Listing
December 2014

Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study.

PLoS One 2014 9;9(4):e93715. Epub 2014 Apr 9.

Department of Neurology, Medical University of Graz, Graz, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz, Austria.

Background: Extrapolations from previous cross-sectional fMRI studies suggest cerebral functional changes with progression of Multiple Sclerosis (MS), but longitudinal studies are scarce. We assessed brain activation changes over time in MS patients using a cognitive fMRI paradigm and examined correlations with clinical and cognitive status and brain morphology.

Methods: 13 MS patients and 15 healthy controls (HC) underwent MRI including fMRI (go/no-go task), neurological and neuropsychological exams at baseline (BL) and follow-up (FU; minimum 12, median 20 months). We assessed estimates of and changes in fMRI activation, total brain and subcortical grey matter volumes, cortical thickness, and T2-lesion load. Bland-Altman (BA) plots served to assess fMRI signal variability.

Results: Cognitive and disability levels remained largely stable in the patients. With the fMRI task, both at BL and FU, patients compared to HC showed increased activation in the insular cortex, precuneus, cerebellum, posterior cingulate cortex, and occipital cortex. At BL, patients vs. HC also had lower caudate nucleus, thalamus and putamen volumes. Over time, patients (but not HC) demonstrated fMRI activity increments in the left inferior parietal lobule. These correlated with worse single-digit-modality test (SDMT) performance. BA-plots attested to reproducibility of the fMRI task. In the patients, the right caudate nucleus decreased in volume which again correlated with worsening SDMT performance.

Conclusions: Given preserved cognitive performance, the increased activation at BL in the patients may be viewed as largely adaptive. In contrast, the negative correlation with SDMT performance suggests increasing parietal activation over time to be maladaptive. Several areas with purported relevance for cognition showed decreased volumes at BL and right caudate nucleus volume decline correlated with decreasing SDMT performance. This highlights the dynamics of functional changes and the strategic importance of specific brain areas for cognitive processes in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093715PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981758PMC
January 2015

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

Authors:
Cornelius A Rietveld Sarah E Medland Jaime Derringer Jian Yang Tõnu Esko Nicolas W Martin Harm-Jan Westra Konstantin Shakhbazov Abdel Abdellaoui Arpana Agrawal Eva Albrecht Behrooz Z Alizadeh Najaf Amin John Barnard Sebastian E Baumeister Kelly S Benke Lawrence F Bielak Jeffrey A Boatman Patricia A Boyle Gail Davies Christiaan de Leeuw Niina Eklund Daniel S Evans Rudolf Ferhmann Krista Fischer Christian Gieger Håkon K Gjessing Sara Hägg Jennifer R Harris Caroline Hayward Christina Holzapfel Carla A Ibrahim-Verbaas Erik Ingelsson Bo Jacobsson Peter K Joshi Astanand Jugessur Marika Kaakinen Stavroula Kanoni Juha Karjalainen Ivana Kolcic Kati Kristiansson Zoltán Kutalik Jari Lahti Sang H Lee Peng Lin Penelope A Lind Yongmei Liu Kurt Lohman Marisa Loitfelder George McMahon Pedro Marques Vidal Osorio Meirelles Lili Milani Ronny Myhre Marja-Liisa Nuotio Christopher J Oldmeadow Katja E Petrovic Wouter J Peyrot Ozren Polasek Lydia Quaye Eva Reinmaa John P Rice Thais S Rizzi Helena Schmidt Reinhold Schmidt Albert V Smith Jennifer A Smith Toshiko Tanaka Antonio Terracciano Matthijs J H M van der Loos Veronique Vitart Henry Völzke Jürgen Wellmann Lei Yu Wei Zhao Jüri Allik John R Attia Stefania Bandinelli François Bastardot Jonathan Beauchamp David A Bennett Klaus Berger Laura J Bierut Dorret I Boomsma Ute Bültmann Harry Campbell Christopher F Chabris Lynn Cherkas Mina K Chung Francesco Cucca Mariza de Andrade Philip L De Jager Jan-Emmanuel De Neve Ian J Deary George V Dedoussis Panos Deloukas Maria Dimitriou Guðny Eiríksdóttir Martin F Elderson Johan G Eriksson David M Evans Jessica D Faul Luigi Ferrucci Melissa E Garcia Henrik Grönberg Vilmundur Guðnason Per Hall Juliette M Harris Tamara B Harris Nicholas D Hastie Andrew C Heath Dena G Hernandez Wolfgang Hoffmann Adriaan Hofman Rolf Holle Elizabeth G Holliday Jouke-Jan Hottenga William G Iacono Thomas Illig Marjo-Riitta Järvelin Mika Kähönen Jaakko Kaprio Robert M Kirkpatrick Matthew Kowgier Antti Latvala Lenore J Launer Debbie A Lawlor Terho Lehtimäki Jingmei Li Paul Lichtenstein Peter Lichtner David C Liewald Pamela A Madden Patrik K E Magnusson Tomi E Mäkinen Marco Masala Matt McGue Andres Metspalu Andreas Mielck Michael B Miller Grant W Montgomery Sutapa Mukherjee Dale R Nyholt Ben A Oostra Lyle J Palmer Aarno Palotie Brenda W J H Penninx Markus Perola Patricia A Peyser Martin Preisig Katri Räikkönen Olli T Raitakari Anu Realo Susan M Ring Samuli Ripatti Fernando Rivadeneira Igor Rudan Aldo Rustichini Veikko Salomaa Antti-Pekka Sarin David Schlessinger Rodney J Scott Harold Snieder Beate St Pourcain John M Starr Jae Hoon Sul Ida Surakka Rauli Svento Alexander Teumer Henning Tiemeier Frank J A van Rooij David R Van Wagoner Erkki Vartiainen Jorma Viikari Peter Vollenweider Judith M Vonk Gérard Waeber David R Weir H-Erich Wichmann Elisabeth Widen Gonneke Willemsen James F Wilson Alan F Wright Dalton Conley George Davey-Smith Lude Franke Patrick J F Groenen Albert Hofman Magnus Johannesson Sharon L R Kardia Robert F Krueger David Laibson Nicholas G Martin Michelle N Meyer Danielle Posthuma A Roy Thurik Nicholas J Timpson André G Uitterlinden Cornelia M van Duijn Peter M Visscher Daniel J Benjamin David Cesarini Philipp D Koellinger

Science 2013 Jun 30;340(6139):1467-71. Epub 2013 May 30.

Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, Netherlands.

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
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http://dx.doi.org/10.1126/science.1235488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751588PMC
June 2013

The molecular genetic architecture of self-employment.

PLoS One 2013 4;8(4):e60542. Epub 2013 Apr 4.

Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, The Netherlands.

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σ(g)(2)/σ(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10(-5) were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617140PMC
November 2013

Abnormalities of resting state functional connectivity are related to sustained attention deficits in MS.

PLoS One 2012 17;7(8):e42862. Epub 2012 Aug 17.

Medical University of Graz, Department of Neurology, Graz, Austria.

Objectives: Resting state (RS) functional MRI recently identified default network abnormalities related to cognitive impairment in MS. fMRI can also be used to map functional connectivity (FC) while the brain is at rest and not adhered to a specific task. Given the importance of the anterior cingulate cortex (ACC) for higher executive functioning in MS, we here used the ACC as seed-point to test for differences and similarities in RS-FC related to sustained attention between MS patients and controls.

Design: Block-design rest phases of 3 Tesla fMRI data were analyzed to assess RS-FC in 31 patients (10 clinically isolated syndromes, 16 relapsing-remitting, 5 secondary progressive MS) and 31 age- and gender matched healthy controls (HC). Participants underwent extensive cognitive testing.

Observations: In both groups, signal changes in several brain areas demonstrated significant correlation with RS-activity in the ACC. These comprised the posterior cingulate cortex (PCC), insular cortices, the right caudate, right middle temporal gyrus, angular gyri, the right hippocampus, and the cerebellum. Compared to HC, patients showed increased FC between the ACC and the left angular gyrus, left PCC, and right postcentral gyrus. Better cognitive performance in the patients was associated with increased FC to the cerebellum, middle temporal gyrus, occipital pole, and the angular gyrus.

Conclusion: We provide evidence for adaptive changes in RS-FC in MS patients compared to HC in a sustained attention network. These results extend and partly mirror findings of task-related fMRI, suggesting FC may increase our understanding of cognitive dysfunction in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042862PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422320PMC
April 2013

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Authors:
Louise V Wain Germaine C Verwoert Paul F O'Reilly Gang Shi Toby Johnson Andrew D Johnson Murielle Bochud Kenneth M Rice Peter Henneman Albert V Smith Georg B Ehret Najaf Amin Martin G Larson Vincent Mooser David Hadley Marcus Dörr Joshua C Bis Thor Aspelund Tõnu Esko A Cecile J W Janssens Jing Hua Zhao Simon Heath Maris Laan Jingyuan Fu Giorgio Pistis Jian'an Luan Pankaj Arora Gavin Lucas Nicola Pirastu Irene Pichler Anne U Jackson Rebecca J Webster Feng Zhang John F Peden Helena Schmidt Toshiko Tanaka Harry Campbell Wilmar Igl Yuri Milaneschi Jouke-Jan Hottenga Veronique Vitart Daniel I Chasman Stella Trompet Jennifer L Bragg-Gresham Behrooz Z Alizadeh John C Chambers Xiuqing Guo Terho Lehtimäki Brigitte Kühnel Lorna M Lopez Ozren Polašek Mladen Boban Christopher P Nelson Alanna C Morrison Vasyl Pihur Santhi K Ganesh Albert Hofman Suman Kundu Francesco U S Mattace-Raso Fernando Rivadeneira Eric J G Sijbrands Andre G Uitterlinden Shih-Jen Hwang Ramachandran S Vasan Thomas J Wang Sven Bergmann Peter Vollenweider Gérard Waeber Jaana Laitinen Anneli Pouta Paavo Zitting Wendy L McArdle Heyo K Kroemer Uwe Völker Henry Völzke Nicole L Glazer Kent D Taylor Tamara B Harris Helene Alavere Toomas Haller Aime Keis Mari-Liis Tammesoo Yurii Aulchenko Inês Barroso Kay-Tee Khaw Pilar Galan Serge Hercberg Mark Lathrop Susana Eyheramendy Elin Org Siim Sõber Xiaowen Lu Ilja M Nolte Brenda W Penninx Tanguy Corre Corrado Masciullo Cinzia Sala Leif Groop Benjamin F Voight Olle Melander Christopher J O'Donnell Veikko Salomaa Adamo Pio d'Adamo Antonella Fabretto Flavio Faletra Sheila Ulivi Fabiola M Del Greco Maurizio Facheris Francis S Collins Richard N Bergman John P Beilby Joseph Hung A William Musk Massimo Mangino So-Youn Shin Nicole Soranzo Hugh Watkins Anuj Goel Anders Hamsten Pierre Gider Marisa Loitfelder Marion Zeginigg Dena Hernandez Samer S Najjar Pau Navarro Sarah H Wild Anna Maria Corsi Andrew Singleton Eco J C de Geus Gonneke Willemsen Alex N Parker Lynda M Rose Brendan Buckley David Stott Marco Orru Manuela Uda Melanie M van der Klauw Weihua Zhang Xinzhong Li James Scott Yii-Der Ida Chen Gregory L Burke Mika Kähönen Jorma Viikari Angela Döring Thomas Meitinger Gail Davies John M Starr Valur Emilsson Andrew Plump Jan H Lindeman Peter A C 't Hoen Inke R König Janine F Felix Robert Clarke Jemma C Hopewell Halit Ongen Monique Breteler Stéphanie Debette Anita L Destefano Myriam Fornage Gary F Mitchell Nicholas L Smith Hilma Holm Kari Stefansson Gudmar Thorleifsson Unnur Thorsteinsdottir Nilesh J Samani Michael Preuss Igor Rudan Caroline Hayward Ian J Deary H-Erich Wichmann Olli T Raitakari Walter Palmas Jaspal S Kooner Ronald P Stolk J Wouter Jukema Alan F Wright Dorret I Boomsma Stefania Bandinelli Ulf B Gyllensten James F Wilson Luigi Ferrucci Reinhold Schmidt Martin Farrall Tim D Spector Lyle J Palmer Jaakko Tuomilehto Arne Pfeufer Paolo Gasparini David Siscovick David Altshuler Ruth J F Loos Daniela Toniolo Harold Snieder Christian Gieger Pierre Meneton Nicholas J Wareham Ben A Oostra Andres Metspalu Lenore Launer Rainer Rettig David P Strachan Jacques S Beckmann Jacqueline C M Witteman Jeanette Erdmann Ko Willems van Dijk Eric Boerwinkle Michael Boehnke Paul M Ridker Marjo-Riitta Jarvelin Aravinda Chakravarti Goncalo R Abecasis Vilmundur Gudnason Christopher Newton-Cheh Daniel Levy Patricia B Munroe Bruce M Psaty Mark J Caulfield Dabeeru C Rao Martin D Tobin Paul Elliott Cornelia M van Duijn

Nat Genet 2011 Sep 11;43(10):1005-11. Epub 2011 Sep 11.

Department of Health Sciences, University of Leicester, Leicester, UK.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
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http://dx.doi.org/10.1038/ng.922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445021PMC
September 2011

Heterogeneity in age-related white matter changes.

Acta Neuropathol 2011 Aug 25;122(2):171-85. Epub 2011 Jun 25.

Division of Special Neurology, Department of Neurology, Medical University of Graz, Austria.

White matter changes occur endemically in routine magnetic resonance imaging (MRI) scans of elderly persons. MRI appearance and histopathological correlates of white matter changes are heterogeneous. Smooth periventricular hyperintensities, including caps around the ventricular horns, periventricular lining and halos are likely to be of non-vascular origin. They relate to a disruption of the ependymal lining with subependymal widening of the extracellular space and have to be differentiated from subcortical and deep white matter abnormalities. For the latter a distinction needs to be made between punctate, early confluent and confluent types. Although punctate white matter lesions often represent widened perivascular spaces without substantial ischemic tissue damage, early confluent and confluent lesions correspond to incomplete ischemic destruction. Punctate abnormalities on MRI show a low tendency for progression, while early confluent and confluent changes progress rapidly. The causative and modifying pathways involved in the occurrence of sporadic age-related white matter changes are still incompletely understood, but recent microarray and genome-wide association approaches increased the notion of pathways that might be considered as targets for therapeutic intervention. The majority of differentially regulated transcripts in white matter lesions encode genes associated with immune function, cell cycle, proteolysis, and ion transport. Genome-wide association studies identified six SNPs mapping to a locus on chromosome 17q25 to be related to white matter lesion load in the general population. We also report first and preliminary data that demonstrate apolipoprotein E (ApoE) immunoreactivity in white matter lesions and support epidemiological findings indicating that ApoE is another factor possibly related to white matter lesion occurrence. Further insights come from modern MRI techniques, such as diffusion tensor and magnetization transfer imaging, as they provide tools for the characterization of normal-appearing brain tissue beyond what can be expected from standard MRI scans. There is a need for additional pre- and postmortem studies in humans, including these new imaging techniques.
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http://dx.doi.org/10.1007/s00401-011-0851-xDOI Listing
August 2011

Cognitively preserved MS patients demonstrate functional differences in processing neutral and emotional faces.

Brain Imaging Behav 2011 Dec;5(4):241-51

Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria.

The ability to recognize emotional facial expressions is crucial to adequate social behavior. Previous studies have suggested deficits in emotion recognition in multiple sclerosis (MS). These deficits were accompanied by several confounders including cognitive or visual impairments, disease duration, and depression. In our study we used functional MRI (fMRI) to test for potential early adaptive changes in only mildly disabled MS patients performing an emotion recognition task including the facial expressions of the emotions anger, fear and disgust. Fifteen relapsing-remitting MS patients with a median Expanded Disability Status Scale (EDSS) score of 2 (range: 0-3.5) and 15 healthy controls (HC) matched for age, gender, and education underwent behavioral (BERT: behavioral emotion recognition test; BRB-N: Brief Repeatable Battery for neuropsychological tests, WCST: Wisconsin Card Sorting Test) and clinical assessments (BDI: Beck Depression Inventory). Conventional MRI at 3.0T served to assess whole-brain volume, white matter, gray matter, cerebrospinal fluid, and T2-lesion load; during fMRI, participants were confronted with neutral, scrambled, angry, disgusted, and fearful faces, and houses. In the absence of differences in cognitive performance and in the ability to accurately recognize distinct emotional facial expressions, MS patients demonstrated excess fMRI activations during facial recognition compared to HC. These differences concerned the posterior cingulate cortex (PCC) and precuneus for anger and disgust contrasted to neutral faces, and the occipital fusiform gyri and the anterior CC for neutral faces versus houses. This study provides first evidence for excess activation during processing of higher order visual stimuli of emotional content in the absence of emotional, visual or cognitive behavior abnormalities already in earlier stages of MS.
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http://dx.doi.org/10.1007/s11682-011-9128-1DOI Listing
December 2011

White matter hyperintensities alter functional organization of the motor system.

Neurobiol Aging 2012 Jan 17;33(1):197.e1-9. Epub 2010 Aug 17.

Department of Neurology, Medical University of Graz, Graz, Austria.

Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.06.005DOI Listing
January 2012

Brain motor system function in a patient with complete spinal cord injury following extensive brain-computer interface training.

Exp Brain Res 2008 Sep 1;190(2):215-23. Epub 2008 Jul 1.

Department of Neurology, Medical University, Auenbruggerplatz 22, 8036, Graz, Austria.

Although several features of brain motor function appear to be preserved even in chronic complete SCI, previous functional MRI (fMRI) studies have also identified significant derangements such as a strongly reduced volume of activation, a poor modulation of function and abnormal activation patterns. It might be speculated that extensive motor imagery training may serve to prevent such abnormalities. We here report on a unique patient with a complete traumatic SCI below C5 who learned to elicit electroencephalographic signals beta-bursts in the midline region upon imagination of foot movements. This enabled him to use a neuroprosthesis and to "walk from thought" in a virtual environment via a brain-computer interface (BCI). We here used fMRI at 3T during imagined hand and foot movements to investigate the effects of motor imagery via persistent BCI training over 8 years on brain motor function and compared these findings to a group of five untrained healthy age-matched volunteers during executed and imagined movements. We observed robust primary sensorimotor cortex (SMC) activity in expected somatotopy in the tetraplegic patient upon movement imagination while such activation was absent in healthy untrained controls. Sensorimotor network activation with motor imagery in the patient (including SMC contralateral to and the cerebellum ipsilateral to the imagined side of movement as well as supplementary motor areas) was very similar to the pattern observed with actual movement in the controls. We interpret our findings as evidence that BCI training as a conduit of motor imagery training may assist in maintaining access to SMC in largely preserved somatopy despite complete deafferentation.
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http://dx.doi.org/10.1007/s00221-008-1465-yDOI Listing
September 2008