Katrin Hegenscheid

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

A Genome-Wide Association Study Identifies Five Loci Influencing Facial Morphology in Europeans

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

Current Smoking and Reduced Gray Matter Volume—a Voxel-Based Morphometry Study

Nicotine modulates prefrontal processing when tested with functional imaging. Previous studies on changes in regional brain volumes in small samples, reporting different life-time exposure to nicotine, identified reduced volume in smokers in prefrontal areas but reported controversial results for other areas. We investigated the association of cigarette smoking and regional gray and white matter volume by using voxel-based morphometry (VBM) for T1-weighted high-resolution magnetic resonance imaging in 315 current-smokers and 659 never-smokers from the representative Study of Health in Pomerania (SHIP). Our study showed that in current-smokers smoking is significantly associated with gray matter volume loss in the prefrontal cortex, the anterior cingulate cortex, the insula, and the olfactory gyrus. White matter volumes were not relevantly reduced in current-smokers. In current-smokers, we found associations of gray matter loss and smoking exposure (pack-years) in the prefrontal cortex, the anterior and middle cingulate cortex, and the superior temporal and angular gyrus, which however did not stand corrections for multiple testing. We confirmed associations between smoking and gray matter differences in the prefrontal cortex, the anterior cingulate cortex and the insula in the general population of Pomerania (Germany). For the first time, we identified differences in brain volumes in the olfactory gyrus. Other cerebral regions did not show significant differences when correcting for multiple comparisons within the whole brain. The regions of structural deficits might be involved in addictive behavior and withdrawal symptoms, whereas further investigations have to show if the observed atrophies were caused by smoking itself or are preexisting differences between smoking and non-smoking individuals.

Laser Ablation of Metastatic Lesions of the Lung: Long-Term Outcome

OBJECTIVE Pulmonary metastatic lesions are present in 20-54% of all patients who die of cancer. Surgical studies have shown that local management of distant tumor metastasis as part of multimodal cancer therapy improves survival. Minimally invasive procedures such as thermal ablation are still to prove their clinical relevance. The aim of this study was to monitor therapeutic outcome and long-term results after percutaneous laser-induced thermal ablation. SUBJECTS AND METHODS Sixty-four patients with metastasis to the lung underwent laser-induced thermal ablation in an ongoing prospective study. A total of 129 percutaneous procedures were performed to manage a total of 108 lung lesions. The median tumor size was 2.0 cm (range, 0.4-8.5 cm). Adequate management of all known individual tumor correlates was critical for definitive patient therapy. The Kaplan-Meier method was used to calculate survival and recurrence rates. RESULTS Definitive management of initial pulmonary disease was achieved in 31 of 64 patients. The 1-, 2-, 3-, 4-, and 5-year survival rates after ablative therapy were 81%, 59%, 44%, 44%, and 27%. The median progression-free interval was 7.4 months. There were no therapy-related deaths. Pneumothorax occurred in 38% of the patients, necessitating periprocedural drainage in 5% of all cases. Parenchymal bleeding (13% of cases) always was self-limited. CONCLUSION Laser ablative therapy for pulmonary metastasis is a promising option in multimodal cancer therapy. The procedure is safe and effective. The initial clinical outcome data strongly suggest that this technique has the potential to improve survival among selected patients.

Laser Ablation of Liver Metastases from Colorectal Cancer with MR Thermometry: 5-Year Survival

PURPOSE To determine technical success, technique effectiveness, complications, and survival after laser ablation of liver metastases from colorectal cancer. MATERIALS AND METHODS Eighty-seven consecutive patients (65 men and 22 women; mean age, 62.8 years) with 180 liver metastases from colorectal carcinoma were included between 1998 and 2005. They underwent laser ablation with magnetic resonance (MR) thermometry in 170 sessions. Indications for laser ablation were locally unresectable tumors (16.1%), metastases in both liver lobes (34.5%), and refusal of surgery and/or general contraindications to surgery (49.4%). Technical success, technique effectiveness, and complication and survival rates were evaluated retrospectively. RESULTS Technical success was achieved in 178 of 180 sessions (99%). Follow-up after 24-48 hours demonstrated an effectiveness rate of 85.6%. Local tumor progression rate was 10% after 6 months. Major complications included large pleural effusion, large subcapsular hematoma, abscess, large pneumothorax, pleuritis with fever, intrahepatic hemorrhage, and biloma. Mean survival from the time of diagnosis of the primary tumor was 50.6 months for all patients treated (95% CI, 44.9-56.3 months). Median survival time was 54 months and survival rates were 95.7% at 1 year, 86.2% at 2 years, 72.4% at 3 years, 50.1% at 4 years, and 33.4% at 5 years. The mean survival time after the first treatment was 31.1 months (95% CI, 26.9-35.3 months). CONCLUSIONS Laser ablation of liver metastases of colorectal cancer with MR thermometry appears safe and efficacious. Although the results are encouraging, direct comparison with other ablative modalities in a prospective clinical trial would be necessary to definitely show one modality is superior.

Whole-Body MR Imaging in the German National Cohort: Rationale, Design, and Technical Background

PURPOSE To detail the rationale, design, and future perspective of implementing whole-body magnetic resonance (MR) imaging in the German National Cohort, a large multicentric population-based study. MATERIALS AND METHODS All institutional review boards approved the study, and informed consent is obtained before study enrollment. Participants are enrolled from a random sample of the general population at five dedicated imaging sites among 18 recruitment centers. MR imaging facilities are equipped with identical 3.0-T imager technology and use uniform MR protocols. Imager-specific hardware and software settings remained constant over the study period. On-site and centralized measures of image quality enable monitoring of completeness of the acquisitions and quality of each of the MR sequences. Certified radiologists read all MR imaging studies for presence of incidental findings according to predefined algorithms. RESULTS Over a 4-year period, six participants per day are examined at each center, totaling a final imaging cohort of approximately 30 000 participants. The MR imaging protocol is identical for each site and comprises a set of 12 native series to cover neurologic, cardiovascular, thoracoabdominal, and musculoskeletal imaging phenotypes totaling approximately 1 hour of imaging time. A dedicated analysis platform as part of a central imaging core incorporates a thin client-based integrative and modular data handling platform to enable multicentric off-site image reading for incidental findings. Scientific analysis will be pursued on a per-project hypothesis-driven basis. CONCLUSION Population-based whole-body MR imaging as part of the German National Cohort will serve to compile a comprehensive image repository, will provide insight into physiologic variants and subclinical disease burden, and has the potential to enable identification of novel imaging biomarkers of risk.

White matter hyperintensities and imaging patterns of brain ageing in the general population

White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimers disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimers disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimers disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimers disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia.

Normal Dynamic MRI Enhancement Patterns of the Upper Abdominal Organs: Gadoxetic Acid Compared With Gadobutrol

OBJECTIVE The purpose of this study was to investigate whether, at dynamic MRI of the upper abdominal organs, contrast enhancement with gadoxetic acid, a hepatobiliary contrast agent, is comparable with that achieved with an extracellular contrast agent. SUBJECTS AND METHODS Dynamic gadoxetic acid-enhanced MRI of the pancreas, spleen, kidney, liver, and abdominal aorta was performed on 50 patients; dynamic gadobutrol-enhanced MRI was performed on a control group of 50 patients; and the images were compared. Dynamic imaging with a T1-weighted volumetric interpolated breath-hold examination gradient-echo sequence (TR/TE, 3.35/1.35; flip angle, 12 degrees ) was performed before and 20 (arterial phase), 55 (portal venous phase), and 90 (hepatic venous phase) seconds after bolus injection of gadoxetic acid (0.25 mmol/mL) or gadobutrol (1.0 mmol/mL). Signal-to-noise ratios and enhancement indexes were calculated for each organ and time. RESULTS All MR images in both groups were of diagnostic quality. During the early dynamic phases, significantly lower mean enhancement indexes were found in the gadoxetic acid group than in the gadobutrol group in the pancreas (portal venous phase, 0.66, 1.39, p <or= 0.001; hepatic venous phase, 0.51, 1.36, p <or= 0.001), spleen (portal venous phase, 1.54, 2.41, p <or= 0.001; hepatic venous phase, 1.19, 2.23, p <or= 0.001), renal cortex (portal venous phase, 1.76, 2.63, p <or= 0.001; hepatic venous phase, 1.60, 2.63, p <or= 0.001), and liver (portal venous phase, 0.76, 0.94, p = 0.016; hepatic venous phase, 0.76, 1.04, p <or= 0.001). In the abdominal aorta, the mean enhancement index was greater after bolus injection of gadoxetic acid (arterial phase, 3.33, 2.24, p <or= 0.005). CONCLUSION Early dynamic MRI of the upper abdominal organs, especially the spleen, pancreas, and kidney, benefits from the higher gadolinium concentration of gadobutrol than in the organ-specific contrast agent gadoxetic acid. Higher protein binding resulting in increased relaxivity of gadoxetic acid compensates for the low gadolinium concentration in the abdominal aorta.

Alexithymia and brain gray matter volumes in a general population sample

Alexithymia is perceived as a personality construct involving deficits in the cognitive processing of emotion. Brain areas that process emotions might be structurally altered in affected people. Subjects from the Study of Health in Pomerania who underwent whole body magnetic resonance imaging were investigated. After quality control procedures 2,589 subjects with Toronto Alexithymia Scale 20 (TAS‐20) data and interview‐based information on major depressive disorder (MDD) were available. After exclusion of study participants who were older than 65 years or had MDD in their lifetime, 1,685 subjects were included in the voxel‐based morphometric (VBM 8) analyses. In whole‐brain analyses, the TAS‐20 total score was associated with less gray matter (GM) volumes of the bilateral dorsal anterior cingulate cortex (dACC). The TAS‐20 factor scale difficulty identifying feelings (DIF) was associated with less GM volume in three clusters: dACC, left middle and inferior temporal gyrus, left fusiform gyrus and cerebellum. The lower GM volume in the left fusiform gyrus was specific for females. Absolute GM volume analyses also revealed associations between the factor scales difficulty describing feelings, external orientated thinking and the dACC. Adjustment for current symptoms of anxiety and depression did not change the effects sizes substantially. In conclusion, lower GM volume in the dACC represents the major structural correlate of alexithymia. Associations with DIF suggest a prominent involvement of left temporal areas. These areas represent language and semantic processing and might be involved in the cognitive processing of emotions and the conscious identification of feelings. Hum Brain Mapp 35:5932–5945, 2014.

Measurement and genetics of human subcortical and hippocampal asymmetries in large datasets

Functional and anatomical asymmetries are prevalent features of the human brain, linked to gender, handedness, and cognition. However, little is known about the neurodevelopmental processes involved. In zebrafish, asymmetries arise in the diencephalon before extending within the central nervous system. We aimed to identify genes involved in the development of subtle, left‐right volumetric asymmetries of human subcortical structures using large datasets. We first tested the feasibility of measuring left‐right volume differences in such large‐scale samples, as assessed by two automated methods of subcortical segmentation (FSL|FIRST and FreeSurfer), using data from 235 subjects who had undergone MRI twice. We tested the agreement between the first and second scan, and the agreement between the segmentation methods, for measures of bilateral volumes of six subcortical structures and the hippocampus, and their volumetric asymmetries. We also tested whether there were biases introduced by left‐right differences in the regional atlases used by the methods, by analyzing left‐right flipped images. While many bilateral volumes were measured well (scan‐rescan r = 0.6–0.8), most asymmetries, with the exception of the caudate nucleus, showed lower repeatabilites. We meta‐analyzed genome‐wide association scan results for caudate nucleus asymmetry in a combined sample of 3,028 adult subjects but did not detect associations at genome‐wide significance (P < 5 × 10−8). There was no enrichment of genetic association in genes involved in left‐right patterning of the viscera. Our results provide important information for researchers who are currently aiming to carry out large‐scale genome‐wide studies of subcortical and hippocampal volumes, and their asymmetries. Hum Brain Mapp 35:3277–3289, 2014.