Matthews PM

References (4)

Title : Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study - Kasperaviciute_2010_Brain_133_2136
Author(s) : Kasperaviciute D , Catarino CB , Heinzen EL , Depondt C , Cavalleri GL , Caboclo LO , Tate SK , Jamnadas-Khoda J , Chinthapalli K , Clayton LM , Shianna KV , Radtke RA , Mikati MA , Gallentine WB , Husain AM , Alhusaini S , Leppert D , Middleton LT , Gibson RA , Johnson MR , Matthews PM , Hosford D , Heuser K , Amos L , Ortega M , Zumsteg D , Wieser HG , Steinhoff BJ , Kramer G , Hansen J , Dorn T , Kantanen AM , Gjerstad L , Peuralinna T , Hernandez DG , Eriksson KJ , Kalviainen RK , Doherty CP , Wood NW , Pandolfo M , Duncan JS , Sander JW , Delanty N , Goldstein DB , Sisodiya SM
Ref : Brain , 133 :2136 , 2010
Abstract : Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
ESTHER : Kasperaviciute_2010_Brain_133_2136
PubMedSearch : Kasperaviciute_2010_Brain_133_2136
PubMedID: 20522523

Title : Common variants conferring risk of schizophrenia - Stefansson_2009_Nature_460_744
Author(s) : Stefansson H , Ophoff RA , Steinberg S , Andreassen OA , Cichon S , Rujescu D , Werge T , Pietilainen OP , Mors O , Mortensen PB , Sigurdsson E , Gustafsson O , Nyegaard M , Tuulio-Henriksson A , Ingason A , Hansen T , Suvisaari J , Lonnqvist J , Paunio T , Borglum AD , Hartmann A , Fink-Jensen A , Nordentoft M , Hougaard D , Norgaard-Pedersen B , Bottcher Y , Olesen J , Breuer R , Moller HJ , Giegling I , Rasmussen HB , Timm S , Mattheisen M , Bitter I , Rethelyi JM , Magnusdottir BB , Sigmundsson T , Olason P , Masson G , Gulcher JR , Haraldsson M , Fossdal R , Thorgeirsson TE , Thorsteinsdottir U , Ruggeri M , Tosato S , Franke B , Strengman E , Kiemeney LA , Melle I , Djurovic S , Abramova L , Kaleda V , Sanjuan J , de Frutos R , Bramon E , Vassos E , Fraser G , Ettinger U , Picchioni M , Walker N , Toulopoulou T , Need AC , Ge D , Yoon JL , Shianna KV , Freimer NB , Cantor RM , Murray R , Kong A , Golimbet V , Carracedo A , Arango C , Costas J , Jonsson EG , Terenius L , Agartz I , Petursson H , Nothen MM , Rietschel M , Matthews PM , Muglia P , Peltonen L , St Clair D , Goldstein DB , Stefansson K , Collier DA
Ref : Nature , 460 :744 , 2009
Abstract : Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
ESTHER : Stefansson_2009_Nature_460_744
PubMedSearch : Stefansson_2009_Nature_460_744
PubMedID: 19571808

Title : Cholinergic agonism alters cognitive processing and enhances brain functional connectivity in patients with multiple sclerosis - Cader_2009_J.Psychopharmacol_23_686
Author(s) : Cader S , Palace J , Matthews PM
Ref : J Psychopharmacol , 23 :686 , 2009
Abstract : The aim of this study is to define mechanisms underlying the pharmacological effects of brain cholinesterase inhibition on cognitive function in patients with multiple sclerosis (MS). Both a Stroop task and an N-back task were used to probe the changes in brain activity using functional magnetic resonance imaging (fMRI) in a single (investigator)-blind, crossover treatment design studying 15 patients with multiple sclerosis (12 relapsing remitting, 3 secondary progressive) taking rivastigmine (4.5 mg po bid) and domperidone (10 mg po qd) or domperidone alone. Administration of rivastigmine increased Stroop functional magnetic resonance imaging activation in the right inferior frontal gyrus for the Stroop task (P < 0.05, corrected). Incremental functional magnetic resonance imaging activation with progressively greater N-back task difficulty was enhanced by rivastigmine in prefrontal and parietal cortical regions (P < 0.01, ANOVA). Functional connectivity analysis of the N-back functional magnetic resonance imaging data based on correlations between pair-wise interregional activations showed increased connectivity between left to right prefrontal, anterior cingulate to left prefrontal and right parietal to right prefrontal regions with rivastigmine (P < 0.05, corrected). Although there were no statistically significant changes in the neuropsychological task performance with rivastigmine in this small study, 11 of 15 patients showed improvements, whereas only 4 of 15 patients showed decline in performance (P = 0.07). With regard to the previous data, these findings suggest different patterns of brain response to lower dose acute and higher dose chronic administration of rivastigmine in patients with multiple sclerosis. They showed that rivastigmine enhances the prefrontal function and alters the functional connectivity associated with cognition. We interpret this as evidence for greater efficiency of brain information transfer that should increase confidence in a potentially beneficial clinical therapeutic effect.
ESTHER : Cader_2009_J.Psychopharmacol_23_686
PubMedSearch : Cader_2009_J.Psychopharmacol_23_686
PubMedID: 18635705

Title : Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine - Parry_2003_Brain_126_2750
Author(s) : Parry AM , Scott RB , Palace J , Smith S , Matthews PM
Ref : Brain , 126 :2750 , 2003
Abstract : One explanation for the weak relationship between neuropsychological deficits and conventional measures of disease burden in multiple sclerosis is that brain 'plasticity' allows adaptive reorganization of cognitive functions to limit impairment, despite injury. We have tested this hypothesis. Ten patients with multiple sclerosis and 11 healthy controls were studied using a functional MRI (fMRI) counting Stroop task. The two subject groups had comparable performances, but a predominantly left medial prefrontal region [Brodmann area (BA) 8/9/10] was more active during the task in patients than in controls (corrected P < 0.001), while a right frontal region (including BA 45 and the basal ganglia) was more active in controls than in patients (corrected P = 0.004). The magnitude of the differences correlated with the normalized brain parenchymal volume, a measure of disease burden (r = -0.72, P = 0.02). We then tested the effects of acute administration of rivastigmine, a central cholinesterase inhibitor, on patterns of brain activation. In five out of five multiple sclerosis patients there was a relative normalization of the abnormal Stroop-associated brain activation, although no change in the patterns of brain activation was found in any of four healthy controls given the drug and tested in the same way. We suggest that recruitment of medial prefrontal cortex is a form of adaptive brain plasticity that compensates, in part, for relative deficits in processing related to the reduced right prefrontal cortex activity with multiple sclerosis. This functional plasticity is modulated by cholinergic agonism and must arise from potentially highly dynamic mechanisms such as the 'unmasking' of latent pathways.
ESTHER : Parry_2003_Brain_126_2750
PubMedSearch : Parry_2003_Brain_126_2750
PubMedID: 12958082