Publications by authors named "Stephan Seiler"

76 Publications

Anatomically Standardized Detection of MRI Atrophy Patterns in Early-Stage Alzheimer's Disease.

Brain Sci 2021 Nov 11;11(11). Epub 2021 Nov 11.

Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

MRI studies have consistently identified atrophy patterns in Alzheimer's disease (AD) through a whole-brain voxel-based analysis, but efforts to investigate morphometric profiles using anatomically standardized and automated whole-brain ROI analyses, performed at the individual subject space, are still lacking. In this study we aimed (i) to utilize atlas-derived measurements of cortical thickness and subcortical volumes, including of the hippocampal subfields, to identify atrophy patterns in early-stage AD, and (ii) to compare cognitive profiles at baseline and during a one-year follow-up of those previously identified morphometric AD subtypes to predict disease progression. Through a prospectively recruited multi-center study, conducted at four Austrian sites, 120 patients were included with probable AD, a disease onset beyond 60 years and a clinical dementia rating of ≤1. Morphometric measures of T1-weighted images were obtained using FreeSurfer. A principal component and subsequent cluster analysis identified four morphometric subtypes, including (i) hippocampal predominant (30.8%), (ii) hippocampal-temporo-parietal (29.2%), (iii) parieto-temporal (hippocampal sparing, 20.8%) and (iv) hippocampal-temporal (19.2%) atrophy patterns that were associated with phenotypes differing predominately in the presentation and progression of verbal memory and visuospatial impairments. These morphologically distinct subtypes are based on standardized brain regions, which are anatomically defined and freely accessible so as to validate its diagnostic accuracy and enhance the prediction of disease progression.
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http://dx.doi.org/10.3390/brainsci11111491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615991PMC
November 2021

Functional (un-)Coupling: Impairment, Compensation, and Future Progression in Alzheimer's Disease.

Clin EEG Neurosci 2021 Oct 18:15500594211052208. Epub 2021 Oct 18.

Department of Neurology, 31475Medical University of Graz, Graz, Austria.

Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age:  = 73.8 years;  = 9.0). Of these, 68 patients ( = 73.9 years;  = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (β = .340;  < .001; β = .274;  = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (β = .329;  = .035) those with greater functional coupling in interhemispheric connections declined more (β = -.402;  = .010). These findings suggest an important role of functional coupling mechanisms in left anterior-posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.
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http://dx.doi.org/10.1177/15500594211052208DOI Listing
October 2021

Prevalence of incidental brain MRI findings of clinical relevance in a diverse Hispanic/Latino population.

J Neuroimaging 2021 Nov 19;31(6):1166-1175. Epub 2021 Jul 19.

Departments of Radiology, Psychiatry and Behavioral Sciences and The Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine and Montefiore Health System, Bronx, NY, USA.

Background And Purpose: There is limited literature on the prevalence of incidental brain MRI findings in the Hispanic/Latino population, despite their increased prevalence of vascular disease and undertreatment of chronic conditions. The purpose of our study was to determine the prevalence of clinically relevant incidental findings on brain MRI examinations obtained as a part of the Study of Latinos-Investigation of NeuroCognitive Aging MRI (SOL-INCA-MRI) study.

Methods: Brain MRI examinations were obtained on 1389 participants in the SOL-INCA-MRI study, a cross-sectional ancillary study of the Hispanic Community Health Study, Study of Latinos, which is a longitudinal, community-based study. Study design of SOL-INCA-MRI involves imaging cognitively normal and participants with mild cognitive impairment. Brain MRI findings were categorized as Level 1 (normal), Level 1.5 (findings of unclear medical significance), Level 2 (potential medical concern), or Level 3 (medically urgent). This article focuses on Level 2 and Level 3 findings.

Results: The average age of the sample was 60.8 years (+/- 10.3 years), 66.1% were females. Level 2 and 3 findings were identified in 117 participants, (8.4%), of which 109 (7.8%) were recommended for medical follow-up (Level 2), and 8 (0.6%) were recommended for immediate medical attention (Level 3). Brain MRI findings consisted of chronic infarction in 33 (2.4%), vascular abnormality in 27 (1.9%), intracranial mass in 20 (1.4%), other intracranial findings in 28 (2.0%), and skull base/extracranial findings in 26 (1.9%) patients.

Conclusion: Incidental findings of clinical relevance were common among SOL-INCA-MRI participants, but rarely required urgent medical intervention.
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http://dx.doi.org/10.1111/jon.12910DOI Listing
November 2021

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Minor Structural Differences in the Cervical Spine Between Patients With Cervical Dystonia and Age-Matched Healthy Controls.

Front Neurol 2020 29;11:472. Epub 2020 May 29.

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

Cervical dystonia is the most common form of focal dystonia. The frequency and pattern of degenerative changes of the cervical spine in patients with cervical dystonia and their relation to clinical symptoms remain unclear as no direct comparison to healthy controls has been performed yet. Here, we used magnetic resonance imaging (MRI) to investigate (1) whether structural abnormalities of the cervical spine are more common in patients with cervical dystonia compared to age-matched healthy controls, (2) if there are clinical predictors for abnormalities on MRI, and (3) to calculate the inter-rater reliability of the respective radiological scales. Twenty-five consecutive patients with cervical dystonia and 20 age-matched healthy controls were included in the study. MRI scans of the cervical spine were analyzed separately by three experienced raters blinded to clinical information, applying different MRI rating scales. Structural abnormalities were compared between groups for upper, middle, and lower cervical spine segments. The associations between scores differentiating both groups and clinical parameters were assessed in dystonia patients. Additionally, inter-rater reliability of the MRI scales was calculated. Comparing structural abnormalities, we found minor differences in the middle cervical spine, indicated by a higher MRI total score in patients but no significant correlation between clinical parameters and MRI changes. Inter-rater reliability was satisfying for most of the MRI rating scales. Our results do not provide evidence for a role of MRI of the cervical spine in the routine work-up of patients with cervical dystonia in the absence of specific clinical signs or symptoms.
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http://dx.doi.org/10.3389/fneur.2020.00472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272577PMC
May 2020

Total gray matter volume is reduced in individuals with bipolar disorder currently treated with atypical antipsychotics.

J Affect Disord 2020 01 19;260:722-727. Epub 2019 Sep 19.

Department of Psychiatry and Psychotherapy, Medical University of Graz, Auenbruggerplatz 31, A-8036, Graz, Austria.

Background/aims: Recent evidence indicates that the intake of atypical antipsychotics (AAP) is associated with gray matter abnormalities in patients with psychiatric disorders. We explored if patients with bipolar disorder (BD) who are medicated with AAP exhibit total gray matter volume (TGV) reduction compared to BD individuals not medicated with AAP and healthy controls (HC).

Methods: In a cross-sectional design, 124 individuals with BD and 86 HC underwent 3T-MRI of the brain and clinical assessment as part of our BIPFAT-study. The TGV was estimated using Freesurfer. We used univariate covariance analysis (ANCOVA) to test for normalized TGV differences and controlled for covariates.

Results: ANCOVA results indicated that 75 BD individuals taking AAP had significantly reduced normalized TGV as compared to 49 BD not taking AAP (F = 9.995, p = .002., Eta = 0.084) and 86 HC (F = 7.577, p = .007, Eta = 0.046).

Limitations: Our cross-sectional results are not suited to draw conclusions about causality. We have no clear information on treatment time and baseline volumes before drug treatment in the studied subjects. We cannot exclude that patients received different psychopharmacologic medications prior to the study point. We did not included dosages into the calculation. Many BD individuals received combinations of psychopharmacotherapy across drug classes. We did not have records displaying quantitative alcohol consumption and drug abuse in our sample.

Conclusions: Our data provide further evidence for the impact of AAP on brain structure in BD. Longitudinal studies are needed to investigate the causal directions of the proposed relationships.
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http://dx.doi.org/10.1016/j.jad.2019.09.068DOI Listing
January 2020

Control of Development, Secondary Metabolism and Light-Dependent Carotenoid Biosynthesis by the Velvet Complex of .

Genetics 2019 07 8;212(3):691-710. Epub 2019 May 8.

Department of Biology, Maynooth University, Co. Kildare, W23 F2H6, Ireland

is an established reference organism to investigate carotene biosynthesis and light regulation. However, there is little evidence of its capacity to produce secondary metabolites. Here, we report the role of the fungal-specific regulatory velvet complexes in development and secondary metabolism (SM) in Three velvet proteins VE-1, VE-2, VOS-1, and a putative methyltransferase LAE-1 show light-independent nucleocytoplasmic localization. Two distinct velvet complexes, a heterotrimeric VE-1/VE-2/LAE-1 and a heterodimeric VE-2/VOS-1 are found The heterotrimer-complex, which positively regulates sexual development and represses asexual sporulation, suppresses siderophore coprogen production under iron starvation conditions. The VE-1/VE-2 heterodimer controls carotene production. VE-1 regulates the expression of >15% of the whole genome, comprising mainly regulatory and developmental features. We also studied intergenera functions of the velvet complex through complementation of , , , mutants with their orthologs , , , and , respectively. Expression of VE-1 and VE-2 in successfully substitutes the developmental and SM functions of VeA and VelB by forming two functional chimeric velvet complexes , VelB/VE-1/LaeA and VE-2/VeA/LaeA, respectively. Reciprocally, expression of restores the phenotypes of the mutant. All velvet proteins heterologously expressed in are localized to the nuclear fraction independent of light. These data highlight the conservation of the complex formation in and However, they also underline the intergenera similarities and differences of velvet roles according to different life styles, niches and ontogenetic processes.
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http://dx.doi.org/10.1534/genetics.119.302277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614901PMC
July 2019

Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans.

PLoS Genet 2019 03 18;15(3):e1008053. Epub 2019 Mar 18.

Biology Department, Maynooth University, Maynooth, Co. Kildare, Ireland.

Eukaryotic striatin forms striatin-interacting phosphatase and kinase (STRIPAK) complexes that control many cellular processes including development, cellular transport, signal transduction, stem cell differentiation and cardiac functions. However, detailed knowledge of complex assembly and its roles in stress responses are currently poorly understood. Here, we discovered six striatin (StrA) interacting proteins (Sips), which form a heptameric complex in the filamentous fungus Aspergillus nidulans. The complex consists of the striatin scaffold StrA, the Mob3-type kinase coactivator SipA, the SIKE-like protein SipB, the STRIP1/2 homolog SipC, the SLMAP-related protein SipD and the catalytic and regulatory phosphatase 2A subunits SipE (PpgA), and SipF, respectively. Single and double deletions of the complex components result in loss of multicellular light-dependent fungal development, secondary metabolite production (e.g. mycotoxin Sterigmatocystin) and reduced stress responses. sipA (Mob3) deletion is epistatic to strA deletion by supressing all the defects caused by the lack of striatin. The STRIPAK complex, which is established during vegetative growth and maintained during the early hours of light and dark development, is mainly formed on the nuclear envelope in the presence of the scaffold StrA. The loss of the scaffold revealed three STRIPAK subcomplexes: (I) SipA only interacts with StrA, (II) SipB-SipD is found as a heterodimer, (III) SipC, SipE and SipF exist as a heterotrimeric complex. The STRIPAK complex is required for proper expression of the heterotrimeric VeA-VelB-LaeA complex which coordinates fungal development and secondary metabolism. Furthermore, the STRIPAK complex modulates two important MAPK pathways by promoting phosphorylation of MpkB and restricting nuclear shuttling of MpkC in the absence of stress conditions. SipB in A. nidulans is similar to human suppressor of IKK-ε(SIKE) protein which supresses antiviral responses in mammals, while velvet family proteins show strong similarity to mammalian proinflammatory NF-KB proteins. The presence of these proteins in A. nidulans further strengthens the hypothesis that mammals and fungi use similar proteins for their immune response and secondary metabolite production, respectively.
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http://dx.doi.org/10.1371/journal.pgen.1008053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438568PMC
March 2019

White Matter Hyperintensities in Alzheimer's Disease: A Lesion Probability Mapping Study.

J Alzheimers Dis 2019 ;68(2):789-796

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

Background/objective: Higher white matter hyperintensity (WMH) load has been reported in Alzheimer's disease (AD) patients in different brain regions when compared to controls. We aimed to assess possible differences of WMH spatial distribution between AD patients and age-matched controls by means of lesion probability maps.

Methods: The present study included MRI scans of 130 probable AD patients with a mean age of 73.4±8.2 years from the Prospective Dementia Registry Austria Study and 130 age-matched healthy controls (HC) from the Austrian Stroke Prevention Family Study. Risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and smoking were assessed. Manually segmented FLAIR WMH masks were non-linearly registered to a template and voxel-based probability mapping was performed.

Results: There were no significant between-group differences in cardiovascular risk factors and WMH volume. AD patients showed a significantly higher likelihood of having WMH in a bilateral periventricular distribution than controls before and after correcting for age, sex, cardiovascular risk factors, and ventricular volume (p≤0.05; threshold-free cluster enhancement corrected). There was no significant association between the periventricular WMH volume and cognitive decline of AD patients.

Conclusion: In AD, WMH were preferentially found in a periventricular location but the volume of lesions was unrelated to cognitive decline in our study irrespective of lesion location.
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http://dx.doi.org/10.3233/JAD-180982DOI Listing
July 2020

Neuroimaging markers of global cognition in early Alzheimer's disease: A magnetic resonance imaging-electroencephalography study.

Brain Behav 2019 01 27;9(1):e01197. Epub 2018 Dec 27.

Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet Glostrup, Glostrup, Denmark.

Introduction: Magnetic resonance imaging (MRI) and electroencephalography (EEG) are a promising means to an objectified assessment of cognitive impairment in Alzheimer's disease (AD). Individually, however, these modalities tend to lack precision in both AD diagnosis and AD staging. A joint MRI-EEG approach that combines structural with functional information has the potential to overcome these limitations.

Materials And Methods: This cross-sectional study systematically investigated the link between MRI and EEG markers and the global cognitive status in early AD. We hypothesized that the joint modalities would identify cognitive deficits with higher accuracy than the individual modalities. In a cohort of 111 AD patients, we combined MRI measures of cortical thickness and regional brain volume with EEG measures of rhythmic activity, information processing and functional coupling in a generalized multiple regression model. Machine learning classification was used to evaluate the markers' utility in accurately separating the subjects according to their cognitive score.

Results: We found that joint measures of temporal volume, cortical thickness, and EEG slowing were well associated with the cognitive status and explained 38.2% of ifs variation. The inclusion of the covariates age, sex, and education considerably improved the model. The joint markers separated the subjects with an accuracy of 84.7%, which was considerably higher than by using individual modalities.

Conclusions: These results suggest that including joint MRI-EEG markers may be beneficial in the diagnostic workup, thus allowing for adequate treatment. Further studies in larger populations, with a longitudinal design and validated against functional-metabolic imaging are warranted to confirm the results.
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http://dx.doi.org/10.1002/brb3.1197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346656PMC
January 2019

Nigral iron deposition in common tremor disorders.

Mov Disord 2019 01 10;34(1):129-132. Epub 2018 Dec 10.

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

Objective: We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties.

Methods: Mean nigral R2* rates were measured in 40 patients with tremor-dominant Parkinson's disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls.

Results: Tremor-dominant PD patients had significantly higher nigral R2* values (34.1 ± 5.7) than those with tremor in dystonia (30.0 ± 3.9), essential tremor (30.6 ± 4.8), and controls (30.0 ± 2.8). An R2* threshold of 31.15 separated tremor-dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non-PD tremor patients was 67.5% and 60%.

Conclusion: Iron content in the substantia nigra is significantly higher in tremor-dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590652PMC
January 2019

Cerebral tract integrity relates to white matter hyperintensities, cortex volume, and cognition.

Neurobiol Aging 2018 12 9;72:14-22. Epub 2018 Aug 9.

Department of Neurology, Center for Neurosciences, University of California at Davis, Davis, CA, USA; Imaging of Dementia and Aging (IDeA) Laboratory, University of California at Davis, Davis, CA, USA.

We examined the relationship among white matter (WM) tract integrity, WM hyperintensities (WMH), lobar gray matter (GM) volumes, and cognition in the cross-sectional Framingham Offspring Study. Six hundred eighty participants (71.7 ± 7.7 years) completed cognitive testing and magnetic resonance imaging. Diffusion tensor imaging probabilistic tractography was used to reconstruct major WM tracts. We computed tract-specific mean fractional anisotropy (FA) and tract-specific WMH ratio. Linear regressions identified relations between tracts and lobar GM volumes. Partial least squares regression examined associations between integrity of combined tracts, lobar GM volumes and cognition, including scores of memory and processing speed. Five tracts were particularly vulnerable to WMH, and tract-specific WMH volumes were inversely associated with tract-specific FA (p values < 0.05). Tract-specific FA related to lobar GM volumes. Memory was associated with lobar GM, while processing speed related to both tract integrity and lobar GM volumes. We conclude that subtle microstructural WM tract degeneration relates to specific lobar GM atrophy. The integrity of associated WM tracts and GM lobes differentially impacts memory and processing speed.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242702PMC
December 2018

Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society.

J Alzheimers Dis 2018 ;63(1):103-114

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

Background: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results.

Objective: Analysis of known and hypothesized factors of CB in home care of dementia patients.

Methods: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis).

Results: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions.

Conclusion: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.
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http://dx.doi.org/10.3233/JAD-170657DOI Listing
August 2019

A comprehensive analysis of resting state fMRI measures to classify individual patients with Alzheimer's disease.

Neuroimage 2018 02 14;167:62-72. Epub 2017 Nov 14.

Leiden University, Institute of Psychology, the Netherlands, Wassenaarseweg 52, 2333 AK, Leiden, The Netherlands; Leiden University Medical Center, Department of Radiology, the Netherlands, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, the Netherlands, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Alzheimer's disease (AD) patients show altered patterns of functional connectivity (FC) on resting state functional magnetic resonance imaging (RSfMRI) scans. It is yet unclear which RSfMRI measures are most informative for the individual classification of AD patients. We investigated this using RSfMRI scans from 77 AD patients (MMSE = 20.4 ± 4.5) and 173 controls (MMSE = 27.5 ± 1.8). We calculated i) FC matrices between resting state components as obtained with independent component analysis (ICA), ii) the dynamics of these FC matrices using a sliding window approach, iii) the graph properties (e.g., connection degree, and clustering coefficient) of the FC matrices, and iv) we distinguished five FC states and administered how long each subject resided in each of these five states. Furthermore, for each voxel we calculated v) FC with 10 resting state networks using dual regression, vi) FC with the hippocampus, vii) eigenvector centrality, and viii) the amplitude of low frequency fluctuations (ALFF). These eight measures were used separately as predictors in an elastic net logistic regression, and combined in a group lasso logistic regression model. We calculated the area under the receiver operating characteristic curve plots (AUC) to determine classification performance. The AUC values ranged between 0.51 and 0.84 and the highest were found for the FC matrices (0.82), FC dynamics (0.84) and ALFF (0.82). The combination of all measures resulted in an AUC of 0.85. We show that it is possible to obtain moderate to good AD classification using RSfMRI scans. FC matrices, FC dynamics and ALFF are most discriminative and the combination of all the resting state measures improves classification accuracy slightly.
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http://dx.doi.org/10.1016/j.neuroimage.2017.11.025DOI Listing
February 2018

Individual classification of Alzheimer's disease with diffusion magnetic resonance imaging.

Neuroimage 2017 05 16;152:476-481. Epub 2017 Mar 16.

Institute of Psychology, Leiden University, The Netherlands; Department of Radiology, Leiden University, The Netherlands; Leiden Institute for Brain and Cognition, The Netherlands.

Diffusion magnetic resonance imaging (MRI) is a powerful non-invasive method to study white matter integrity, and is sensitive to detect differences in Alzheimer's disease (AD) patients. Diffusion MRI may be able to contribute towards reliable diagnosis of AD. We used diffusion MRI to classify AD patients (N=77), and controls (N=173). We use different methods to extract information from the diffusion MRI data. First, we use the voxel-wise diffusion tensor measures that have been skeletonised using tract based spatial statistics. Second, we clustered the voxel-wise diffusion measures with independent component analysis (ICA), and extracted the mixing weights. Third, we determined structural connectivity between Harvard Oxford atlas regions with probabilistic tractography, as well as graph measures based on these structural connectivity graphs. Classification performance for voxel-wise measures ranged between an AUC of 0.888, and 0.902. The ICA-clustered measures ranged between an AUC of 0.893, and 0.920. The AUC for the structural connectivity graph was 0.900, while graph measures based upon this graph ranged between an AUC of 0.531, and 0.840. All measures combined with a sparse group lasso resulted in an AUC of 0.896. Overall, fractional anisotropy clustered into ICA components was the best performing measure. These findings may be useful for future incorporation of diffusion MRI into protocols for AD classification, or as a starting point for early detection of AD using diffusion MRI.
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http://dx.doi.org/10.1016/j.neuroimage.2017.03.025DOI Listing
May 2017

SymB and SymC, two membrane associated proteins, are required for Epichloë festucae hyphal cell-cell fusion and maintenance of a mutualistic interaction with Lolium perenne.

Mol Microbiol 2017 02 14;103(4):657-677. Epub 2016 Dec 14.

Institute of Fundamental Sciences, Massey University, Palmerston North, 4442, New Zealand.

Cell-cell fusion in fungi is required for colony formation, nutrient transfer and signal transduction. Disruption of genes required for hyphal fusion in Epichloë festucae, a mutualistic symbiont of Lolium grasses, severely disrupts the host interaction phenotype. They examined whether symB and symC, the E. festucae homologs of Podospora anserina self-signaling genes IDC2 and IDC3, are required for E. festucae hyphal fusion and host symbiosis. Deletion mutants of these genes were defective in hyphal cell fusion, formed intra-hyphal hyphae, and had enhanced conidiation. SymB-GFP and SymC-mRFP1 localize to plasma membrane, septa and points of hyphal cell fusion. Plants infected with ΔsymB and ΔsymC strains were severely stunted. Hyphae of the mutants colonized vascular bundles, were more abundant than wild type in the intercellular spaces and formed intra-hyphal hyphae. Although these phenotypes are identical to those previously observed for cell wall integrity MAP kinase mutants no difference was observed in the basal level of MpkA phosphorylation or its cellular localization in the mutant backgrounds. Both genes contain binding sites for the transcription factor ProA. Collectively these results show that SymB and SymC are key components of a conserved signaling network for E. festucae to maintain a mutualistic symbiotic interaction within L. perenne.
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http://dx.doi.org/10.1111/mmi.13580DOI Listing
February 2017

Free to Choose? Reform, Choice, and Consideration Sets in the English National Health Service.

Am Econ Rev 2016 Nov;106(11):3521-57

Business School, Imperial College London, London, UK.

Choice in public services is controversial. We exploit a reform in the English National Health Service to assess the effect of removing constraints on patient choice. We estimate a demand model that explicitly captures the removal of the choice constraints imposed on patients. We find that, post-removal, patients became more responsive to clinical quality. This led to a modest reduction in mortality and a substantial increase in patient welfare. The elasticity of demand faced by hospitals increased substantially post- reform and we find evidence that hospitals responded to the enhanced incentives by improving quality. This suggests greater choice can raise quality.
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http://dx.doi.org/10.1257/aer.20121532DOI Listing
November 2016

Quantitative Susceptibility Mapping in Parkinson's Disease.

PLoS One 2016 6;11(9):e0162460. Epub 2016 Sep 6.

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

Background: Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely.

Methods: The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables.

Results: Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra.

Conclusion: The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012676PMC
August 2017

Determinants of iron accumulation in the normal aging brain.

Neurobiol Aging 2016 07 13;43:149-55. Epub 2016 Apr 13.

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

In a recent postmortem study, R2* relaxometry in gray matter (GM) of the brain has been validated as a noninvasive measure for iron content in brain tissue. Iron accumulation in the normal aging brain is a common finding and relates to brain maturation and degeneration. The goal of this study was to assess the determinants of iron accumulation during brain aging. The study cohort consisted of 314 healthy community-dwelling participants of the Austrian Stroke Prevention Study. Their age ranged from 38-82 years. Quantitative magnetic resonance imaging was performed on 3T and included R2* mapping, based on a 3D multi-echo gradient echo sequence. The median of R2* values was measured in all GM regions, which were segmented automatically using FreeSurfer. We investigated 25 possible determinants for cerebral iron deposition. These included demographics, brain volume, lifestyle factors, cerebrovascular risk factors, serum levels of iron, and single nucleotide polymorphisms related to iron regulating genes (rs1800562, rs3811647, rs1799945, and rs1049296). The body mass index (BMI) was significantly related to R2* in 15/32 analyzed brain regions with the strongest correlations found in the amygdala (p = 0.0091), medial temporal lobe (p = 0.0002), and hippocampus (p ≤ 0.0001). Further associations to R2* values were found in deep GM for age and smoking. No significant associations were found for gender, GM volume, serum levels of iron, or iron-associated genetic polymorphisms. In conclusion, besides age, the BMI and smoking are the only significant determinants of brain iron accumulation in normally aging subjects. Smoking relates to iron deposition in the basal ganglia, whereas higher BMI is associated with iron content in the neocortex following an Alzheimer-like distribution.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.04.002DOI Listing
July 2016

Combining anatomical, diffusion, and resting state functional magnetic resonance imaging for individual classification of mild and moderate Alzheimer's disease.

Neuroimage Clin 2016 9;11:46-51. Epub 2016 Jan 9.

Institute of Psychology, Leiden University, The Netherlands; Department of Radiology, Leiden University, The Netherlands; Leiden Institute for Brain and Cognition, The Netherlands.

Magnetic resonance imaging (MRI) is sensitive to structural and functional changes in the brain caused by Alzheimer's disease (AD), and can therefore be used to help in diagnosing the disease. Improving classification of AD patients based on MRI scans might help to identify AD earlier in the disease's progress, which may be key in developing treatments for AD. In this study we used an elastic net classifier based on several measures derived from the MRI scans of mild to moderate AD patients (N = 77) from the prospective registry on dementia study and controls (N = 173) from the Austrian Stroke Prevention Family Study. We based our classification on measures from anatomical MRI, diffusion weighted MRI and resting state functional MRI. Our unimodal classification performance ranged from an area under the curve (AUC) of 0.760 (full correlations between functional networks) to 0.909 (grey matter density). When combining measures from multiple modalities in a stepwise manner, the classification performance improved to an AUC of 0.952. This optimal combination consisted of grey matter density, white matter density, fractional anisotropy, mean diffusivity, and sparse partial correlations between functional networks. Classification performance for mild AD as well as moderate AD also improved when using this multimodal combination. We conclude that different MRI modalities provide complementary information for classifying AD. Moreover, combining multiple modalities can substantially improve classification performance over unimodal classification.
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http://dx.doi.org/10.1016/j.nicl.2016.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732186PMC
December 2016

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

Mov Disord 2016 Apr 16;31(4):555-62. Epub 2016 Feb 16.

Sobell Department, UCL Institute of Neurology, London, United Kingdom.

Background: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.

Objectives: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty.

Methods: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor.

Results: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%.

Conclusion: We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice.
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http://dx.doi.org/10.1002/mds.26525DOI Listing
April 2016

Quantifying synchrony patterns in the EEG of Alzheimer's patients with linear and non-linear connectivity markers.

J Neural Transm (Vienna) 2016 Mar 28;123(3):297-316. Epub 2015 Sep 28.

Institute for Mathematical Methods in Economics, Vienna University of Technology, Vienna, Austria.

We analyzed the relation of several synchrony markers in the electroencephalogram (EEG) and Alzheimer's disease (AD) severity as measured by Mini-Mental State Examination (MMSE) scores. The study sample consisted of 79 subjects diagnosed with probable AD. All subjects were participants in the PRODEM-Austria study. Following a homogeneous protocol, the EEG was recorded both in resting state and during a cognitive task. We employed quadratic least squares regression to describe the relation between MMSE and the EEG markers. Factor analysis was used for estimating a potentially lower number of unobserved synchrony factors. These common factors were then related to MMSE scores as well. Most markers displayed an initial increase of EEG synchrony with MMSE scores from 26 to 21 or 20, and a decrease below. This effect was most prominent during the cognitive task and may be owed to cerebral compensatory mechanisms. Factor analysis provided interesting insights in the synchrony structures and the first common factors were related to MMSE scores with coefficients of determination up to 0.433. We conclude that several of the proposed EEG markers are related to AD severity for the overall sample with a wide dispersion for individual subjects. Part of these fluctuations may be owed to fluctuations and day-to-day variability associated with MMSE measurements. Our study provides a systematic analysis of EEG synchrony based on a large and homogeneous sample. The results indicate that the individual markers capture different aspects of EEG synchrony and may reflect cerebral compensatory mechanisms in the early stages of AD.
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http://dx.doi.org/10.1007/s00702-015-1461-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766239PMC
March 2016

Cerebral White Matter Lesions and Affective Episodes Correlate in Male Individuals with Bipolar Disorder.

PLoS One 2015 7;10(8):e0135313. Epub 2015 Aug 7.

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

Background: Cerebral white matter lesions (WML) have been found in normal aging, vascular disease and several neuropsychiatric conditions. Correlations of WML with clinical parameters in BD have been described, but not with the number of affective episodes, illness duration, age of onset and Body Mass Index in a well characterized group of euthymic bipolar adults. Herein, we aimed to evaluate the associations between bipolar course of illness parameters and WML measured with volumetric analysis.

Methods: In a cross-sectional study 100 euthymic individuals with BD as well as 54 healthy controls (HC) were enrolled to undergo brain magnetic resonance imaging using 3T including a FLAIR sequence for volumetric assessment of WML-load using FSL-software. Additionally, clinical characteristics and psychometric measures including Structured Clinical Interview according to DSM-IV, Hamilton-Depression, Young Mania Rating Scale and Beck's Depression Inventory were evaluated.

Results: Individuals with BD had significantly more (F = 3.968, p < .05) WML (Mdn = 3710 mm3; IQR = 2961 mm3) than HC (Mdn = 2185 mm3; IQR = 1665 mm3). BD men (Mdn = 4095 mm3; IQR = 3295 mm3) and BD women (Mdn = 3032 mm3; IQR = 2816 mm3) did not significantly differ as to the WML-load or the number and type of risk factors for WML. However, in men only, the number of manic/hypomanic episodes (r = 0.72; p < .001) as well as depressive episodes (r = 0.51; p < .001) correlated positively with WML-load.

Conclusions: WML-load strongly correlated with the number of manic episodes in male BD patients, suggesting that men might be more vulnerable to mania in the context of cerebral white matter changes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135313PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529150PMC
May 2016

Deletion of Smgpi1 encoding a GPI-anchored protein suppresses sterility of the STRIPAK mutant ΔSmmob3 in the filamentous ascomycete Sordaria macrospora.

Mol Microbiol 2015 Aug 26;97(4):676-97. Epub 2015 May 26.

Institute of Microbiology and Genetics, Department of Genetics of Eukaryotic Microorganisms, Georg-August-University, Göttingen, Germany.

The striatin interacting phosphatase and kinase (STRIPAK) complex, which is composed of striatin, protein phosphatase PP2A and kinases, is required for fruiting-body development and cell fusion in the filamentous ascomycete Sordaria macrospora. Here, we report on the interplay of the glycosylphosphatidylinositol (GPI)-anchored protein SmGPI1 with the kinase activator SmMOB3, a core component of human and fungal STRIPAK complexes. SmGPI1 is conserved among filamentous ascomycetes and was first identified in a yeast two-hybrid screen using SmMOB3 as bait. The physical interaction of SmMOB3 and SmGPI1 was verified by co-immunoprecipitation. In vivo localization and differential centrifugation revealed that SmGPI1 is predominantly secreted and attached to the cell wall but is also associated with mitochondria and appears to be a dual-targeted protein. Deletion of Smgpi1 led to an increased number of fruiting bodies that were normally shaped but reduced in size. In addition, Smmob3 and Smgpi1 genetically interact. In the sterile ΔSmmob3 background deletion of Smgpi1 restores fertility, vegetative growth as well as hyphal-fusion defects. The suppression effect was specific for the ΔSmmob3 mutant as deletion of Smgpi1 in other STRIPAK mutants does not restore fertility.
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http://dx.doi.org/10.1111/mmi.13054DOI Listing
August 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

Common genetic variants influence human subcortical brain structures.

Nature 2015 Apr 21;520(7546):224-9. Epub 2015 Jan 21.

1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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http://dx.doi.org/10.1038/nature14101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393366PMC
April 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

Fungal communication requires the MAK-2 pathway elements STE-20 and RAS-2, the NRC-1 adapter STE-50 and the MAP kinase scaffold HAM-5.

PLoS Genet 2014 Nov 20;10(11):e1004762. Epub 2014 Nov 20.

Institute for Biology II - Molecular Plant Physiology, Albert-Ludwigs University Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs University Freiburg, Freiburg, Germany.

Intercellular communication is critical for the survival of unicellular organisms as well as for the development and function of multicellular tissues. Cell-to-cell signaling is also required to develop the interconnected mycelial network characteristic of filamentous fungi and is a prerequisite for symbiotic and pathogenic host colonization achieved by molds. Somatic cell-cell communication and subsequent cell fusion is governed by the MAK-2 mitogen activated protein kinase (MAPK) cascade in the filamentous ascomycete model Neurospora crassa, yet the composition and mode of regulation of the MAK-2 pathway are currently unclear. In order to identify additional components involved in MAK-2 signaling we performed affinity purification experiments coupled to mass spectrometry with strains expressing functional GFP-fusion proteins of the MAPK cascade. This approach identified STE-50 as a regulatory subunit of the Ste11p homolog NRC-1 and HAM-5 as cell-communication-specific scaffold protein of the MAPK cascade. Moreover, we defined a network of proteins consisting of two Ste20-related kinases, the small GTPase RAS-2 and the adenylate cyclase capping protein CAP-1 that function upstream of the MAK-2 pathway and whose signals converge on the NRC-1/STE-50 MAP3K complex and the HAM-5 scaffold. Finally, our data suggest an involvement of the striatin interacting phosphatase and kinase (STRIPAK) complex, the casein kinase 2 heterodimer, the phospholipid flippase modulators YPK-1 and NRC-2 and motor protein-dependent vesicle trafficking in the regulation of MAK-2 pathway activity and function. Taken together, these data will have significant implications for our mechanistic understanding of MAPK signaling and for homotypic cell-cell communication in fungi and higher eukaryotes.
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http://dx.doi.org/10.1371/journal.pgen.1004762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239118PMC
November 2014

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

Stroke 2014 Dec 6;45(12):3589-96. Epub 2014 Nov 6.

From the Department of Radiology, AA Martinos Center for Biomedical Imaging (H.A., E.M.A., T.B.), Stroke Service, Department of Neurology (H.A., J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (G.A., H.D., A.L., O.M., B.N.); Department of Neurology, Mayo Clinic Rochester, MN (R.D.B.); Department of Neurology (S.N.C., B.B.W.), Center for Public Health Genomics (S.S.R.), and Department of Public Health Sciences (B.B.W.), University of Virginia, Charlottesville; Department of Neurology (J.W.C., S.J.K.) and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine (P.F.M.), University of Maryland School of Medicine, Baltimore; Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-University, München, Germany (M.D., M.L.); Department of Clinical Science, Lund University, Malmö, Sweden (G.E., B.N.); Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar, Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Spain (E.G.-S., J.J.-C., J.R.); Neuroscience Institute, Saint Francis Medical Center, Trenton, NJ (R.P.G., L.R.P.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (K.G.); Institute of Biomedicine (C.J., A.P.) and Institute of Neuroscience and Physiology (K.J.), Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Neurology, University of Miami Miller School of Medicine, FL (M.K., T.R., R.L.S.); Department of Neurology, University of Cincinnati College of Medicine, OH (B.K., D.O.K.); Department of Neurology, Stern Stroke Center, Albert Einstein College of Medicine, Bronx, NY (D.L.L.); Department of Neuroscience and Sensory Organs, Policlinico Hospital Foundation IRCCS Cà Granda, Milan, Italy (S.L.); Department of Neurology, Washington U

Background And Purpose: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium.

Methods: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases.

Results: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75).

Conclusions: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.
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http://dx.doi.org/10.1161/STROKEAHA.114.007362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286169PMC
December 2014

Magnetization transfer ratio relates to cognitive impairment in normal elderly.

Front Aging Neurosci 2014 25;6:263. Epub 2014 Sep 25.

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

Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38-86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia.
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http://dx.doi.org/10.3389/fnagi.2014.00263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174770PMC
October 2014
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