Publications by authors named "Elna-Marie Larsson"

128 Publications

Evaluation of Arterial Spin Labeling MRI-Comparison with O-Water PET on an Integrated PET/MR Scanner.

Diagnostics (Basel) 2021 May 1;11(5). Epub 2021 May 1.

Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden.

Cerebral blood flow (CBF) measurements are of high clinical value and can be acquired non-invasively with no radiation exposure using pseudo-continuous arterial spin labeling (ASL). The aim of this study was to evaluate accordance in resting state CBF between ASL (CBF) and O-water positron emission tomography (PET) (CBF) acquired simultaneously on an integrated 3T PET/MR system. The data comprised ASL and dynamic O-water PET data with arterial blood sampling of eighteen subjects (eight patients with focal epilepsy and ten healthy controls, age 21 to 61 years). O-water PET parametric CBF images were generated using a basis function implementation of the single tissue compartment model. Cortical and subcortical regions were automatically segmented using Freesurfer. Average CBF and CBF in grey matter were 60 ± 20 and 75 ± 22 mL/100 g/min respectively, with a relatively high correlation ( = 0.78, < 0.001). Bland-Altman analysis revealed poor agreement (bias = -15 mL/100 g/min, lower and upper limits of agreements = -16 and 45 mL/100 g/min, respectively) with a negative relationship. Accounting for the negative relationship, the width of the limits of agreement could be narrowed from 61 mL/100 g/min to 35 mL/100 g/min using regression-based limits of agreements. Although a high correlation between CBF and CBF was found, the agreement in absolute CBF values was not sufficient for ASL to be used interchangeably with O-water PET.
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http://dx.doi.org/10.3390/diagnostics11050821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147295PMC
May 2021

Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients - A PET/MR study.

Neuroimage Clin 2021 7;30:102665. Epub 2021 Apr 7.

Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.

Traumatic brain injury (TBI) and repeated sports-related concussions (rSRCs) are associated with an increased risk for neurodegeneration. Autopsy findings of selected cohorts of long-term TBI survivors and rSRC athletes reveal increased tau aggregation and a persistent neuroinflammation. To assess in vivo tau aggregation and neuroinflammation in young adult TBI and rSRC cohorts, we evaluated 9 healthy controls (mean age 26 ± 5 years; 4 males, 5 females), 12 symptomatic athletes (26 ± 7 years; 6 males, 6 females) attaining ≥3 previous SRCs, and 6 moderate-to severe TBI patients (27 ± 7 years; 4 males, 2 females) in a combined positron emission tomography (PET)/magnetic resonance (MR) scanner ≥6 months post-injury. Dual PET tracers, [F]THK5317 for tau aggregation and [C]PK11195 for neuroinflammation/microglial activation, were investigated on the same day. The Repeated Battery Assessment of Neurological Status (RBANS) scores, used for cognitive evaluation, were lower in both the rSRC and TBI groups (p < 0.05). Neurofilament-light (NF-L) levels were increased in plasma and cerebrospinal fluid (CSF; p < 0.05), and serum tau levels lower, in TBI although not in rSRC. In rSRC athletes, PET imaging showed increased neuroinflammation in the hippocampus and tau aggregation in the corpus callosum. In TBI patients, tau aggregation was observed in thalami, temporal white matter and midbrain; widespread neuroinflammation was found e.g. in temporal white matter, hippocampus and corpus callosum. In mixed-sex cohorts of young adult athletes with persistent post-concussion symptoms and in TBI patients, increased tau aggregation and neuroinflammation are observed at ≥6 months post-injury using PET. Studies with extended clinical follow-up, biomarker examinations and renewed PET imaging are needed to evaluate whether these findings progress to a neurodegenerative disorder or if spontaneous resolution is possible.
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http://dx.doi.org/10.1016/j.nicl.2021.102665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091173PMC
April 2021

Visual rating versus volumetry of regional brain atrophy and longitudinal changes over a 5-year period in an elderly population.

Brain Behav 2020 07 20;10(7):e01662. Epub 2020 May 20.

Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.

Introduction: The purpose of our study was to compare visual rating and volumetry of brain atrophy in an elderly population over a 5-year period and compare findings with cognitive test results.

Materials And Methods: Two hundred and one subjects were examined with magnetic resonance imaging (MRI) of the brain. Visual rating and volumetry were performed in all subjects at ages 75 and 80. Cognitive function at both time points was assessed with the Mini-Mental State Examination (MMSE) and Trail Making Tests A and B (TMT-A and TMT-B). Changes in visual rating and volumetry were compared with changes in cognitive test.

Results: A correlation was found between visual rating of medial temporal lobe atrophy (MTA) and hippocampal volumetry at both time points (rs = -.42 and rs = -.49, p < .001, respectively). The correlation between visual rating of posterior atrophy (PA); frontal atrophy (F-GCA) and volumetry of these brain regions was significant only at age 80 (rs = -.16, p = .02 for PA and rpb = .19, p = .006 for F-GCA). Visual rating showed only a minimal progression of regional atrophy at age 80, whereas volumetry showed 2%-5% decrease in volume depending on brain region. Performance in the MMSE, TMT-A, and TMT-B was virtually unchanged between ages 75 and 80.

Conclusion: We found a mild age-associated decrease in regional brain volumes in this healthy cohort with well-preserved cognitive functions. Visual assessment may not be sufficient for detecting mild progression of brain atrophy due to normal aging, whereas volumetry is more sensitive to capture these subtle changes.
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http://dx.doi.org/10.1002/brb3.1662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375085PMC
July 2020

Cerebral Perfusion Does Not Increase after Shunt Surgery for Normal Pressure Hydrocephalus.

J Neuroimaging 2020 05 6;30(3):303-307. Epub 2020 May 6.

Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.

Background And Purpose: Cerebral blood flow (CBF) has been reported to increase after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). The aims of this study were to investigate if CBF, measured using the noninvasive perfusion MRI method arterial spin labeling (ASL), increased after shunt surgery, if postoperative change in CBF correlated with improvement in symptoms, and if baseline CBF data correlated with postoperative outcome.

Methods: Twenty-three patients with iNPH were prospectively included and examined with MRI of the brain and clinical tests of symptoms at baseline. Eighteen of the patients were treated with shunt implantation and were reexamined with clinical tests and MRI 3 months postoperatively. The MRI protocol included a pseudo-continuous ASL sequence for perfusion imaging. The perfusion was measured in 12 manually drawn regions of interest (ROIs).

Results: In the whole sample, CBF did not increase after shunting in any ROI. Preoperative CBF in medial frontal cortex correlated with an improvement in urinary incontinence after shunt surgery, r = .53, P = .022. There were no correlations between change in CBF and change in clinical symptoms postoperatively.

Conclusions: The clinical value of ASL in the work-up of patients with iNPH is uncertain. In this study, ASL could not predict outcome after shunt surgery and there were no correlations between change in CBF and change in clinical symptoms after shunt surgery.
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http://dx.doi.org/10.1111/jon.12702DOI Listing
May 2020

Diagnostic accuracy of the iNPH Radscale in idiopathic normal pressure hydrocephalus.

PLoS One 2020 24;15(4):e0232275. Epub 2020 Apr 24.

Department of Neuroscience, Neurology, Uppsala University Hospital, Uppsala, Sweden.

Background And Purpose: The idiopathic normal pressure hydrocephalus (iNPH) Radscale was developed to standardize the evaluation of radiological signs in iNPH. The purpose of this study was to estimate the diagnostic accuracy of the iNPH Radscale in a sample of "true positive" and "true negative" cases.

Methods: Seventy-five patients with definite iNPH, i.e. who had improved at clinical follow-up one year after ventriculoperitoneal shunt surgery, were compared with 55 asymptomatic individuals from the general population. A radiologist assessed the seven radiological features of the iNPH Radscale in computed tomography of the brain in the patients (preoperatively) and controls.

Results: The iNPH Radscale score was significantly higher in the iNPH group (Median = 10, interquartile range 9-11) than in the control group (Median = 1, interquartile range 1-2) (p <0.001). Receiver operated characteristics analysis yielded an area under the curve of 99.7%, and an iNPH Radscale score ≤ 4 identified those without iNPH, with a sensitivity of 100%, specificity of 96% and overall accuracy of 98.5%.

Conclusions: In this study, iNPH Radscale could accurately discriminate between patients with definite iNPH and asymptomatic individuals over 65 years old. According to the results, a diagnosis of iNPH is very likely in patients with an iNPH Radscale score above 8 and corresponding clinical symptoms. On the other hand, the diagnosis should be questioned when the iNPH Radscale score is below the cut-off level of 4. We conclude that the iNPH Radscale could work as a diagnostic screening tool to detect iNPH. Whether the scale also can be used to predict shunt outcome needs further studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182203PMC
July 2020

Functional connectivity underlying hedonic response to food in female adolescents with atypical AN: the role of somatosensory and salience networks.

Transl Psychiatry 2019 11 7;9(1):276. Epub 2019 Nov 7.

Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.

Atypical anorexia nervosa (AN) usually occurs during adolescence. Patients are often in the normal-weight range at diagnosis; however, they often present with signs of medical complications and severe restraint over eating, body dissatisfaction, and low self-esteem. We investigated functional circuitry underlying the hedonic response in 28 female adolescent patients diagnosed with atypical AN and 33 healthy controls. Participants were shown images of food with high (HC) or low (LC) caloric content in alternating blocks during functional MRI. The HC > LC contrast was calculated. Based on the previous literature on full-threshold AN, we hypothesized that patients would exhibit increased connectivity in areas involved in sensory processing and bottom-up responses, coupled to increased connectivity from areas related to top-down inhibitory control, compared with controls. Patients showed increased connectivity in pathways related to multimodal somatosensory processing and memory retrieval. The connectivity was on the other hand decreased in patients in salience and attentional networks, and in a wide cerebello-occipital network. Our study was the first investigation of food-related neural response in atypical AN. Our findings support higher somatosensory processing in patients in response to HC food images compared with controls, however HC food was less efficient than LC food in engaging patients' bottom-up salient responses, and was not associated with connectivity increases in inhibitory control regions. These findings suggest that the psychopathological mechanisms underlying food restriction in atypical AN differ from full-threshold AN. Elucidating the mechanisms underlying the development and maintenance of eating behavior in atypical AN might help designing specific treatment strategies.
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http://dx.doi.org/10.1038/s41398-019-0617-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838122PMC
November 2019

Neuroimaging, genetic, clinical, and demographic predictors of treatment response in patients with social anxiety disorder.

J Affect Disord 2020 01 20;261:230-237. Epub 2019 Oct 20.

Department of Psychology, Uppsala University, Uppsala, Sweden.

Background: Correct prediction of treatment response is a central goal of precision psychiatry. Here, we tested the predictive accuracy of a variety of pre-treatment patient characteristics, including clinical, demographic, molecular genetic, and neuroimaging markers, for treatment response in patients with social anxiety disorder (SAD).

Methods: Forty-seven SAD patients (mean±SD age 33.9 ± 9.4 years, 24 women) were randomized and commenced 9 weeks' Internet-delivered cognitive behavior therapy (CBT) combined either with the selective serotonin reuptake inhibitor (SSRI) escitalopram (20 mg daily [10 mg first week], SSRI+CBT, n = 24) or placebo (placebo+CBT, n = 23). Treatment responders were defined from the Clinical Global Impression-Improvement scale (CGI-I ≤ 2). Before treatment, patients underwent functional magnetic resonance imaging and the Multi-Source Interference Task taxing cognitive interference. Support vector machines (SVMs) were trained to separate responders from nonresponders based on pre-treatment neural reactivity in the dorsal anterior cingulate cortex (dACC), amygdala, and occipital cortex, as well as molecular genetic, demographic, and clinical data. SVM models were tested using leave-one-subject-out cross-validation.

Results: The best model separated treatment responders (n = 24) from nonresponders based on pre-treatment dACC reactivity (83% accuracy, P = 0.001). Responders had greater pre-treatment dACC reactivity than nonresponders especially in the SSRI+CBT group. No other variable was associated with clinical response or added predictive accuracy to the dACC SVM model.

Limitations: Small sample size, especially for genetic analyses. No replication or validation samples were available.

Conclusions: The findings demonstrate that treatment outcome predictions based on neural cingulate activity, at the individual level, outperform genetic, demographic, and clinical variables for medication-assisted Internet-delivered CBT, supporting the use of neuroimaging in precision psychiatry.
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http://dx.doi.org/10.1016/j.jad.2019.10.027DOI Listing
January 2020

Standardized acquisition and post-processing of dynamic susceptibility contrast perfusion in patients with brain tumors, cerebrovascular disease and dementia: comparability of post-processing software.

Br J Radiol 2020 Jan 24;93(1105):20190543. Epub 2019 Oct 24.

Department of Neuroradiology, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.

Objective: MR-perfusion post-processing still lacks standardization. This study evaluates the results of perfusion analysis with two established software solutions in a large series of patients with different diseases when a highly standardized processing workflow is ensured.

Methods: Multicenter data of 260 patients (80 with brain tumors, 124 with cerebrovascular disease and 56 with dementia examined with the same MR protocol) were analyzed. Raw data sets were processed with two software suites: Olea sphere and NordicICE. Group differences were analyzed with paired -tests and one-way ANOVA.

Results: Perfusion metrics were significantly different for all examined diseases in the unaffected brain for both software suites [ratio cortex/white matter left hemisphere: mean transit time (MTT) 0.991 0.847, < 0.05; relative cerebral bloodflow (rBF) 3.23 4.418, < 0.001; relative cerebral bloodvolume (rBVc) 2.813 3.884, < 0.001; right hemisphere: MTT 1.079 0.854, < 0.05; rBF 3.262 4.378, < 0.001; rBVc 2.762 3.935, < 0.001)]. Perfusion results were also significantly different in patients with stroke (ratio cortex/white matter affected hemisphere: MTT 1.058 0.784; < 0.001), dementia (ratio cortex/white matter left hemisphere: rBVc 1.152 1.795, < 0.001; right hemisphere: rBVc 1.396 1.662, < 0.05) and brain tumors (ratio cortex/whole tumor rBVc: 0.778 0.919, < 0.001 and ratio cortex/tumor hotspot rBVc: 0.529 0.512, < 0.05).

Conclusion: Despite a highly standardized workflow, parametric perfusion maps are depended on the chosen software. Radiologists should consider software related variances when using dynamic susceptibility contrast perfusion for clinical imaging and research.

Advances In Knowledge: This multicenter study compared perfusion parameters calculated by two commercial dynamic susceptibility contrast perfusion post-processing software solutions in different central nervous system disorders with a large sample size and a highly standardized processing workflow. Despite, parametric perfusion maps are depended on the chosen software which impacts clinical imaging and research.
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http://dx.doi.org/10.1259/bjr.20190543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948086PMC
January 2020

A study of neural activity and functional connectivity within the olfactory brain network in Parkinson's disease.

Neuroimage Clin 2019 18;23:101946. Epub 2019 Jul 18.

Department of Surgical Sciences/Radiology, Uppsala University, Uppsala, Sweden.

Olfactory dysfunction is an early manifestation of Parkinson's disease (PD). The present study aimed to illustrate potential differences between PD patients and healthy controls in terms of neural activity and functional connectivity within the olfactory brain network. Twenty PD patients and twenty healthy controls were examined with olfactory fMRI and resting-state fMRI. Data analysis of olfactory fMRI included data-driven tensorial independent component (ICA) and task-driven general linear model (GLM) analyses. Data analysis of resting-state fMRI included probabilistic ICA based on temporal concatenation and functional connectivity analysis within the olfactory network. ICA of olfactory fMRI identified an olfactory network consisting of the posterior piriform cortex, insula, right orbitofrontal cortex and thalamus. Recruitment of this network was less significant for PD patients. GLM analysis revealed significantly lower activity in the insula bilaterally and the right orbitofrontal cortex in PD compared to healthy controls but no significant differences in the olfactory cortex itself. Analysis of resting-state fMRI did not reveal any differences in the functional connectivity within the olfactory, default mode, salience or central executive networks between the two groups. In conclusion, olfactory dysfunction in PD is associated with less significant recruitment of the olfactory brain network. ICA could demonstrate differences in both the olfactory cortex and its main projections, compared to GLM that revealed differences only on the latter. Resting-state fMRI did not reveal any significant differences in functional connectivity within the olfactory, default mode, salience and central executive networks in this cohort.
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http://dx.doi.org/10.1016/j.nicl.2019.101946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661283PMC
August 2020

Diagnostic value of alternative techniques to gadolinium-based contrast agents in MR neuroimaging-a comprehensive overview.

Insights Imaging 2019 Aug 23;10(1):84. Epub 2019 Aug 23.

Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.

Gadolinium-based contrast agents (GBCAs) increase lesion detection and improve disease characterization for many cerebral pathologies investigated with MRI. These agents, introduced in the late 1980s, are in wide use today. However, some non-ionic linear GBCAs have been associated with the development of nephrogenic systemic fibrosis in patients with kidney failure. Gadolinium deposition has also been found in deep brain structures, although it is of unclear clinical relevance. Hence, new guidelines from the International Society for Magnetic Resonance in Medicine advocate cautious use of GBCA in clinical and research practice. Some linear GBCAs were restricted from use by the European Medicines Agency (EMA) in 2017.This review focuses on non-contrast-enhanced MRI techniques that can serve as alternatives for the use of GBCAs. Clinical studies on the diagnostic performance of non-contrast-enhanced as well as contrast-enhanced MRI methods, both well established and newly proposed, were included. Advantages and disadvantages together with the diagnostic performance of each method are detailed. Non-contrast-enhanced MRIs discussed in this review are arterial spin labeling (ASL), time of flight (TOF), phase contrast (PC), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), susceptibility weighted imaging (SWI), and amide proton transfer (APT) imaging.Ten common diseases were identified for which studies reported comparisons of non-contrast-enhanced and contrast-enhanced MRI. These specific diseases include primary brain tumors, metastases, abscess, multiple sclerosis, and vascular conditions such as aneurysm, arteriovenous malformation, arteriovenous fistula, intracranial carotid artery occlusive disease, hemorrhagic, and ischemic stroke.In general, non-contrast-enhanced techniques showed comparable diagnostic performance to contrast-enhanced MRI for specific diagnostic questions. However, some diagnoses still require contrast-enhanced imaging for a complete examination.
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http://dx.doi.org/10.1186/s13244-019-0771-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708018PMC
August 2019

Standardized image evaluation in patients with idiopathic normal pressure hydrocephalus: consistency and reproducibility.

Neuroradiology 2019 Dec 10;61(12):1397-1406. Epub 2019 Aug 10.

Department of Pharmacology and Clinical Neuroscience, Neurology, Östersund, Umeå University, SE-901 87, Umeå, Sweden.

Purpose: Assess the agreement for two investigators between computed tomography (CT) and magnetic resonance imaging (MRI) for seven imaging features included in the iNPH Radscale, a radiological screening tool.

Methods: The study included 35 patients with idiopathic normal pressure hydrocephalus (iNPH) who were treated surgically from 2011 to 2015 at Uppsala University Hospital with preoperative CT and MRI performed with maximum 3 months between scans. Seven features were assessed: Evans' index, temporal horn size, callosal angle, periventricular white matter changes, narrow high convexity sulci, focally enlarged sulci, and enlarged Sylvian fissures. All scans were assessed by two investigators who were blinded to each other's results and to clinical data.

Results: The agreement between CT and MRI was almost perfect for Evans' index, temporal horns, narrow sulci, and Sylvian fissures (kappa and intraclass correlation, 0.84-0.91, p ≤ 0.001). There was substantial to almost perfect agreement for callosal angle and focally enlarged sulci. The concordance between modalities was fair for changes in periventricular white matter.

Conclusion: CT and MRI are equally good for assessing radiological signs associated with iNPH except for periventricular white matter changes, as MRI has superior soft tissue contrast. The other imaging features can be evaluated consistently, and assessments are reproducible independent of modality. Therefore, the iNPH Radscale is applicable to both CT and MRI and may become an important tool for standardized evaluation in the workup in patients with suspected iNPH.
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http://dx.doi.org/10.1007/s00234-019-02273-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848037PMC
December 2019

Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation.

Acta Neurol Scand 2019 Nov 5;140(5):320-327. Epub 2019 Aug 5.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

Material And Methods: Case series of patients with relapsing-remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as "no evidence of disease activity-4," sustained for a period of at least 5 years without any ongoing disease-modifying treatment. Furthermore, MS was considered as "resolved" if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.
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http://dx.doi.org/10.1111/ane.13147DOI Listing
November 2019

A novel radiological classification system for cerebral gliomas: The Brain-Grid.

PLoS One 2019 24;14(1):e0211243. Epub 2019 Jan 24.

Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden.

Purpose: Standard radiological/topographical classifications of gliomas often do not reflect the real extension of the tumor within the lobar-cortical anatomy. Furthermore, these systems do not provide information on the relationship between tumor growth and the subcortical white matter architecture. We propose the use of an anatomically standardized grid system (the Brain-Grid) to merge serial morphological magnetic resonance imaging (MRI) scans with a representative tractographic atlas. Two illustrative cases are presented to show the potential advantages of this classification system.

Methods: MRI scans of 39 patients (WHO grade II and III gliomas) were analyzed with a standardized grid created by intersecting longitudinal lines on the axial, sagittal, and coronal planes. The anatomical landmarks were chosen from an average brain, spatially normalized to the Montreal Neurological Institute (MNI) space and the Talairach space. Major white matter pathways were reconstructed with a deterministic tracking algorithm on a reference atlas and analyzed using the Brain-Grid system.

Results: In all, 48 brain grid voxels (areas defined by 3 coordinates, axial (A), coronal (C), sagittal (S) and numbers from 1 to 4) were delineated in each MRI sequence and on the tractographic atlas. The number of grid voxels infiltrated was consistent, also in the MNI space. The sub-cortical insula/basal ganglia (A3-C2-S2) and the fronto-insular region (A3-C2-S1) were most frequently involved. The inferior fronto-occipital fasciculus, anterior thalamic radiation, uncinate fasciculus, and external capsule were the most frequently associated pathways in both hemispheres.

Conclusions: The Brain-Grid based classification system provides an accurate observational tool in all patients with suspected gliomas, based on the comparison of grid voxels on a morphological MRI and segmented white matter atlas. Important biological information on tumor kinetics including extension, speed, and preferential direction of progression can be observed and even predicted with this system. This novel classification can easily be applied to both prospective and retrospective cohorts of patients and increase our comprehension of glioma behavior.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211243PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345500PMC
November 2019

Preserved white matter microstructure in adolescent patients with atypical anorexia nervosa.

Int J Eat Disord 2019 02 24;52(2):166-174. Epub 2019 Jan 24.

Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.

Objective: Patients with atypical anorexia nervosa (AN) are often in the normal-weight range at presentation; however, signs of starvation and medical instability are not rare. White matter (WM) microstructural correlates of atypical AN have not yet been investigated, leaving an important gap in our knowledge regarding the neural pathogenesis of this disorder.

Method: We investigated WM microstructural integrity in 25 drug-naïve adolescent patients with atypical AN and 25 healthy controls, using diffusion tensor imaging (DTI) with a tract-based spatial statistics (TBSS) approach. Psychological variables related to the eating disorder and depressive symptoms were also evaluated by administering the eating disorder examination questionnaire (EDE-Q) and the Montgomery-Åsberg depression rating scale (MADRS-S) respectively, to all participants.

Results: Patients and controls were in the normal-weight range and did not differ from the body mass index standard deviations for their age. No between groups difference in WM microstructure could be detected.

Discussion: Our findings support the hypothesis that brain structural alterations may not be associated to early-stage atypical AN. These findings also suggest that previous observations of alterations in WM microstructure in full syndrome AN may constitute state-related consequences of severe weight loss. Whether the preservation of WM structure is a pathogenetically discriminant feature of atypical AN or only an effect of a less severe nutritional disturbance, will have to be verified by future studies on larger samples, possibly directly comparing AN and atypical AN.
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http://dx.doi.org/10.1002/eat.23012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590352PMC
February 2019

Reduced resting-state connectivity in areas involved in processing of face-related social cues in female adolescents with atypical anorexia nervosa.

Transl Psychiatry 2018 12 13;8(1):275. Epub 2018 Dec 13.

Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.

Atypical anorexia nervosa (AN) has a high incidence in adolescents and can result in significant morbidity and mortality. Neuroimaging could improve our knowledge regarding the pathogenesis of eating disorders (EDs), however research on adolescents with EDs is limited. To date no neuroimaging studies have been conducted to investigate brain functional connectivity in atypical AN. We investigated resting-state functional connectivity using 3 T MRI in 22 drug-naïve adolescent patients with atypical AN, and 24 healthy controls. Psychological traits related to the ED and depressive symptoms have been assessed using the Eating Disorders Examination Questionnaire (EDE-Q) and the Montgomery-Åsberg Depression Rating Scale self-reported (MADRS-S) respectively. Reduced connectivity was found in patients in brain areas involved in face-processing and social cognition, such as the left putamen, the left occipital fusiform gyrus, and specific cerebellar lobules. The connectivity was, on the other hand, increased in patients compared with controls from the right inferior temporal gyrus to the superior parietal lobule and superior lateral occipital cortex. These areas are involved in multimodal stimuli integration, social rejection and anxiety. Patients scored higher on the EDE-Q and MADRS-S questionnaires, and the MADRS-S correlated with connectivity from the right inferior temporal gyrus to the superior parietal lobule in patients. Our findings point toward a role for an altered development of socio-emotional skills in the pathogenesis of atypical AN. Nonetheless, longitudinal studies will be needed to assess whether these connectivity alterations might be a neural marker of the pathology.
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http://dx.doi.org/10.1038/s41398-018-0333-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293319PMC
December 2018

Dynamic contrast-enhanced magnetic resonance imaging may act as a biomarker for vascular damage in normal appearing brain tissue after radiotherapy in patients with glioblastoma.

Acta Radiol Open 2018 Nov 9;7(11):2058460118808811. Epub 2018 Nov 9.

Department of Radiology, Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising perfusion method and may be useful in evaluating radiation-induced changes in normal-appearing brain tissue.

Purpose: To assess whether radiotherapy induces changes in vascular permeability (K) and the fractional volume of the extravascular extracellular space (V) derived from DCE-MRI in normal-appearing brain tissue and possible relationships to radiation dose given.

Material And Methods: Seventeen patients with glioblastoma treated with radiotherapy and chemotherapy were included; five were excluded because of inconsistencies in the radiotherapy protocol or early drop-out. DCE-MRI, contrast-enhanced three-dimensional (3D) T1-weighted (T1W) images and T2-weighted fluid attenuated inversion recovery (T2-FLAIR) images were acquired before and on average 3.3, 30.6, 101.6, and 185.7 days after radiotherapy. Pre-radiotherapy CE T1W and T2-FLAIR images were segmented into white and gray matter, excluding all non-healthy tissue. K and V were calculated using the extended Kety model with the Parker population-based arterial input function. Six radiation dose regions were created for each tissue type, based on each patient's computed tomography-based dose plan. Mean K and V were calculated over each dose region and tissue type.

Results: Global K and V demonstrated mostly non-significant changes with mean values higher for post-radiotherapy examinations in both gray and white matter compared to pre-radiotherapy. No relationship to radiation dose was found.

Conclusion: Additional studies are needed to validate if K and V derived from DCE-MRI may act as potential biomarkers for acute and early-delayed radiation-induced vascular damages. No dose-response relationship was found.
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http://dx.doi.org/10.1177/2058460118808811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236579PMC
November 2018

Evaluation of zero-echo-time attenuation correction for integrated PET/MR brain imaging-comparison to head atlas and Ge-transmission-based attenuation correction.

EJNMMI Phys 2018 Oct 22;5(1):20. Epub 2018 Oct 22.

Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background: MRI does not offer a direct method to obtain attenuation correction maps as its predecessors (stand-alone PET and PET/CT), and bone visualisation is particularly challenging. Recently, zero-echo-time (ZTE) was suggested for MR-based attenuation correction (AC). The aim of this work was to evaluate ZTE- and atlas-AC by comparison to Ge-transmission scan-based AC. Nine patients underwent brain PET/MR and stand-alone PET scanning using the dopamine transporter ligand C-PE2I. For each of them, two AC maps were obtained from the MR images: an atlas-based, obtained from T1-weighted LAVA-FLEX imaging with cortical bone inserted using a CT-based atlas, and an AC map generated from proton-density-weighted ZTE images. Stand-alone PET Ge-transmission AC map was used as gold standard. PET images were reconstructed using the three AC methods and standardised uptake value (SUV) values for the striatal, limbic and cortical regions, as well as the cerebellum (VOIs) were compared. SUV ratio (SUVR) values normalised for the cerebellum were also assessed. Bias, precision and agreement were calculated; statistical significance was evaluated using Wilcoxon matched-pairs signed-rank test.

Results: Both ZTE- and atlas-AC showed a similar bias of 6-8% in SUV values across the regions. Correlation coefficients with Ge-AC were consistently high for ZTE-AC (r 0.99 for all regions), whereas they were lower for atlas-AC, varying from 0.99 in the striatum to 0.88 in the posterior cortical regions. SUVR showed an overall bias of 2.9 and 0.5% for atlas-AC and ZTE-AC, respectively. Correlations with Ge-AC were higher for ZTE-AC, varying from 0.99 in the striatum to 0.96 in the limbic regions, compared to atlas-AC (0.99 striatum to 0.77 posterior cortex).

Conclusions: Absolute SUV values showed less variability for ZTE-AC than for atlas-AC when compared to Ge-AC, but bias was similar for both methods. This bias is largely caused by higher linear attenuation coefficients in atlas- and ZTE-AC image compared to Ge-images. For SUVR, bias was lower when using ZTE-AC than for atlas-AC. ZTE-AC shows to be a more robust technique than atlas-AC in terms of both intra- and inter-patient variability.
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http://dx.doi.org/10.1186/s40658-018-0220-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196145PMC
October 2018

Z-score maps from low-dose F-FDG PET of the brain in neurodegenerative dementia.

Am J Nucl Med Mol Imaging 2018 20;8(4):239-246. Epub 2018 Aug 20.

Department of Surgical Sciences, Nuclear Medicine and PET, Uppsala University Uppsala, Sweden.

Neuroimaging is a central part of diagnostic work-up of patients with suspected neurodegenerative disease. FDG-PET can reveal pathological changes earlier and more reliably than morphological imaging. Diagnostic accuracy can be improved by constructing 3D SSP Z-score maps, showing patterns of significant deficits. During FDG-PET, the subject receives a moderate but not insignificant dose of ionizing radiation, and a dose reduction with retained image quality is desirable. With lower dose, repeated examinations can become a useful tool for monitoring disease progress and potential effects of disease-modifying interventions. The aim of this study was to evaluate Z-maps created from low-dose and normal-dose FDG-PET of the brain, with quantitative and qualitative methods. Nine patients with neurodegenerative disorders were prospectively enrolled and nine age-matched controls were recruited through advertising. All subjects (n=18) underwent two FDG-PET scans on separate occasions; a routine and a low-dose scan. The routine dosage of FDG was 3 MBq/kg, and low dosage was 0.75 MBq/kg. 3D-SSP images showing Z-scores of < -1.96 were created from 10-minute summations. The study was comprised of a quantitative part comparing the Z-scores, and a qualitative part where experienced nuclear medicine specialists visually assessed the images. Regarding the quantitative part, Bland-Altman analysis showed a slight constant bias (0.206). Regarding qualitative discrimination between patients and controls, the performance between normal- and low-dose were equal, both showing 72% sensitivity, 83% specificity and 78% accuracy. In this study, visual assessment of 3D-SSP Z-score maps from low-dose FDG-PET provided diagnostic information highly comparable to normal-dose, with minor quantitative discrepancies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146163PMC
August 2018

Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity.

Eur J Nucl Med Mol Imaging 2019 03 14;46(3):569-579. Epub 2018 Aug 14.

Department of Neuroscience, Neurology, Uppsala University, University Hospital, S-751 85, Uppsala, Sweden.

Purpose: Oligodendrogliomas are heterogeneous tumors in terms of imaging appearance, and a deeper understanding of the histopathological tumor characteristics in correlation to imaging parameters is needed. We used PET-to-MRI-to-histology co-registration with the aim of studying intra-tumoral C-methionine (MET) uptake in relation to tumor perfusion and the protein expression of histological cell markers in corresponding areas.

Methods: Consecutive histological sections of four tumors covering the entire en bloc-removed tumor were immunostained with antibodies against IDH1-mutated protein (tumor cells), Ki67 (proliferating cells), and CD34 (blood vessels). Software was developed for anatomical landmarks-based co-registration of subsequent histological images, which were overlaid on corresponding MET PET scans and MRI perfusion maps. Regions of interest (ROIs) on PET were selected throughout the entire tumor volume, covering hot spot areas, areas adjacent to hot spots, and tumor borders with infiltrating zone. Tumor-to-normal tissue (T/N) ratios of MET uptake and mean relative cerebral blood volume (rCBV) were measured in the ROIs and protein expression of histological cell markers was quantified in corresponding regions. Statistical correlations were calculated between MET uptake, rCBV, and quantified protein expression.

Results: A total of 84 ROIs were selected in four oligodendrogliomas. A significant correlation (p < 0.05) between MET uptake and tumor cell density was demonstrated in all tumors separately. In two tumors, MET correlated with the density of proliferating cells and vessel cell density. There were no significant correlations between MET uptake and rCBV, and between rCBV and histological cell markers.

Conclusions: The MET uptake in hot spots, outside hotspots, and in infiltrating tumor edges unanimously reflects tumor cell density. The correlation between MET uptake and vessel density and density of proliferating cells is less stringent in infiltrating tumor edges and is probably more susceptible to artifacts caused by larger blood vessels surrounding the tumor. Although based on a limited number of samples, this study provides histological proof for MET as an indicator of tumor cell density and for the lack of statistically significant correlations between rCBV and histological cell markers in oligodendrogliomas.
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http://dx.doi.org/10.1007/s00259-018-4107-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351509PMC
March 2019

Small Vessel Disease on Neuroimaging in a 75-Year-Old Cohort (PIVUS): Comparison With Cognitive and Executive Tests.

Front Aging Neurosci 2018 16;10:217. Epub 2018 Jul 16.

Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.

: Signs of small vessel disease (SVD) are commonly seen on magnetic resonance imaging (MRI) of the brain in cognitively healthy elderly individuals, and the clinical relevance of these are often unclear. We have previously described three different MRI manifestations of SVD as well as cerebral perfusion in a longitudinal study of non-demented 75-year-old subjects. The purpose of the present study was to evaluate the relationship of these findings to cognition and executive function at age 75 and changes after 5 years. : In all, 406 subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study were examined with MRI of the brain at age 75 years. Two-hundred and fifty of the subjects were re-examined 5 years later. White matter hyperintensities (WMHs) and lacunar infarcts (LIs) were assessed on both occasions, but microbleeds (MBs) and perfusion only at age 75. Cognitive function was screened by the Mini Mental State Examination (MMSE). Trail Making Test A and B (TMT-A and TMT-B) were performed at baseline and at follow-up at age 80. : At baseline, 93% performed >27 points in the MMSE. The TMT-B at age 75 was significantly related to WMH visual scoring after adjustment for sex, education and cerebrovascular disease risk factors (+80 s (95% CI 0.3-161 s), < 0.05 for grade 2-3 vs. grade 0). Neither MMSE nor TMT-A was significantly related to WMH scoring. There was no relation between any test performance and WMH volume, white matter volume, number of MBs or brain perfusion at age 75. Subjects who had sustained a new LI ( = 26) showed a greater increase of the time to perform TMT-A at the 5-year follow-up (+25 s vs. +4 s in LI-free subjects, = 0.003). Changes in MMSE or TMT-A and -B test performance between ages 75 and 80 were not related to changes in WMH scoring or volume during the 5 years follow-up, or to brain perfusion at age 75. : In this cognitively healthy community-based population, moderate-severe WMHs and incident LIs on brain MRI in individuals aged 75-80 years were associated with a mild impairment of processing speed and executive function.
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http://dx.doi.org/10.3389/fnagi.2018.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054972PMC
July 2018

Perfusion Magnetic Resonance Imaging Changes in Normal Appearing Brain Tissue after Radiotherapy in Glioblastoma Patients may Confound Longitudinal Evaluation of Treatment Response.

Radiol Oncol 2018 Jun 6;52(2):143-151. Epub 2018 Jun 6.

Department of Radiology, Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background: The aim of this study was assess acute and early delayed radiation-induced changes in normal-appearing brain tissue perfusion as measured with perfusion magnetic resonance imaging (MRI) and the dependence of these changes on the fractionated radiotherapy (FRT) dose level.

Patients And Methods: Seventeen patients with glioma WHO grade III-IV treated with FRT were included in this prospective study, seven were excluded because of inconsistent FRT protocol or missing examinations. Dynamic susceptibility contrast MRI and contrast-enhanced 3D-T1-weighted (3D-T1w) images were acquired prior to and in average (standard deviation): 3.1 (3.3), 34.4 (9.5) and 103.3 (12.9) days after FRT. Pre-FRT 3D-T1w images were segmented into white- and grey matter. Cerebral blood volume (CBV) and cerebral blood flow (CBF) maps were calculated and co-registered patient-wise to pre-FRT 3D-T1w images. Seven radiation dose regions were created for each tissue type: 0-5 Gy, 5-10 Gy, 10-20 Gy, 20-30 Gy, 30-40 Gy, 40-50 Gy and 50-60 Gy. Mean CBV and CBF were calculated in each dose region and normalised (nCBV and nCBF) to the mean CBV and CBF in 0-5 Gy white- and grey matter reference regions, respectively.

Results: Regional and global nCBV and nCBF in white- and grey matter decreased after FRT, followed by a tendency to recover. The response of nCBV and nCBF was dose-dependent in white matter but not in grey matter.

Conclusions: Our data suggest that radiation-induced perfusion changes occur in normal-appearing brain tissue after FRT. This can cause an overestimation of relative tumour perfusion using dynamic susceptibility contrast MRI, and can thus confound tumour treatment evaluation.
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http://dx.doi.org/10.2478/raon-2018-0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043875PMC
June 2018

Olfactory fMRI: Implications of Stimulation Length and Repetition Time.

Chem Senses 2018 07;43(6):389-398

Department of Surgical Sciences/Radiology, Uppsala University, Akademiska sjukhuset Uppsala, Sweden.

Studying olfaction with functional magnetic resonance imaging (fMRI) poses various methodological challenges. This study aimed to investigate the effects of stimulation length and repetition time (TR) on the activation pattern of 4 olfactory brain regions: the anterior and the posterior piriform cortex, the orbitofrontal cortex, and the insula. Twenty-two healthy participants with normal olfaction were examined with fMRI, with 2 stimulation lengths (6 s and 15 s) and 2 TRs (0.901 s and 1.34 s). Data were analyzed using General Linear Model (GLM), Tensorial Independent Component Analysis (TICA), and by plotting the event-related time course of brain activation in the 4 olfactory regions of interest. The statistical analysis of the time courses revealed that short TR was associated with more pronounced signal increase and short stimulation was associated with shorter time to peak signal. Additionally, both long stimulation and short TR were associated with oscillatory time courses, whereas both short stimulation and short TR resulted in more typical time courses. GLM analysis showed that the combination of short stimulation and short TR could result in visually larger activation within these olfactory areas. TICA validated that the tested paradigm was spatially and temporally associated with a functionally connected network that included all 4 olfactory regions. In conclusion, the combination of short stimulation and short TR is associated with higher signal increase and shorter time to peak, making it more amenable to standard GLM-type analyses than long stimulation and long TR, and it should, thus, be preferable for olfactory fMRI.
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http://dx.doi.org/10.1093/chemse/bjy025DOI Listing
July 2018

Cerebral Microbleeds: Imaging and Clinical Significance.

Radiology 2018 Apr;287(1):11-28

From the Affidea Centre de Diagnostic Radiologique de Carouge (CDRC), Geneva, Switzerland (S.H.); Faculty of Medicine, University of Geneva, Geneva, Switzerland (S.H.); Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden (S.H., E.M.L.); Department of Neuroradiology, University Hospital Freiburg, Freiburg, Germany (S.H.); Department of Radiology and Nuclear Medicine and Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (M.W.V.); Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands (J.P.A.K., F.B.); Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, Institute of Neurology, University College London, London, England (H.R.J., F.B.).

Cerebral microbleeds (CMBs), also referred to as microhemorrhages, appear on magnetic resonance (MR) images as hypointense foci notably at T2*-weighted or susceptibility-weighted (SW) imaging. CMBs are detected with increasing frequency because of the more widespread use of high magnetic field strength and of newer dedicated MR imaging techniques such as three-dimensional gradient-echo T2*-weighted and SW imaging. The imaging appearance of CMBs is mainly because of changes in local magnetic susceptibility and reflects the pathologic iron accumulation, most often in perivascular macrophages, because of vasculopathy. CMBs are depicted with a true-positive rate of 48%-89% at 1.5 T or 3.0 T and T2*-weighted or SW imaging across a wide range of diseases. False-positive "mimics" of CMBs occur at a rate of 11%-24% and include microdissections, microaneurysms, and microcalcifications; the latter can be differentiated by using phase images. Compared with postmortem histopathologic analysis, at least half of CMBs are missed with premortem clinical MR imaging. In general, CMB detection rate increases with field strength, with the use of three-dimensional sequences, and with postprocessing methods that use local perturbations of the MR phase to enhance T2* contrast. Because of the more widespread availability of high-field-strength MR imaging systems and growing use of SW imaging, CMBs are increasingly recognized in normal aging, and are even more common in various disorders such as Alzheimer dementia, cerebral amyloid angiopathy, stroke, and trauma. Rare causes include endocarditis, cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and radiation therapy. The presence of CMBs in patients with stroke is increasingly recognized as a marker of worse outcome. Finally, guidelines for adjustment of anticoagulant therapy in patients with CMBs are under development. RSNA, 2018.
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http://dx.doi.org/10.1148/radiol.2018170803DOI Listing
April 2018

Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity.

Front Hum Neurosci 2018 22;12:75. Epub 2018 Feb 22.

Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.

: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward-related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated () gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers. : We have tested WM integrity in 21 male participants genotyped on the risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: "risk tracts", "obesity-associated tracts", and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the "risk-tracts" (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire. : An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the "risk tracts". Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks. : A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the AA risk-allele, and possibly act as a predisposing factor to the development of obesity.
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http://dx.doi.org/10.3389/fnhum.2018.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826967PMC
February 2018

Increase in callosal angle and decrease in ventricular volume after shunt surgery in patients with idiopathic normal pressure hydrocephalus.

J Neurosurg 2018 02;130(1):130-135

4Department of Surgical Sciences, Radiology, Uppsala University, Uppsala; and.

OBJECTIVE Postoperative decrease in ventricle size is usually not detectable either by visual assessment or by measuring the Evans index in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of the present study was to investigate whether the angle between the lateral ventricles (the callosal angle [CA]) increases and ventricular volume decreases after shunt surgery in patients with iNPH. METHODS Magnetic resonance imaging of the brain was performed before and 3 months after shunt surgery in 18 patients with iNPH. The CA and Evans index were measured on T1-weighted 3D MR images, and ventricular volume contralateral to the shunt valve was measured with quantitative MRI. RESULTS The CA was larger postoperatively (mean 78°, 95% CI 69°-87°) than preoperatively (mean 67°, 95% CI 60°-73°; p < 0.001). The volume of the lateral ventricle contralateral to the shunt valve decreased from 73 ml (95% CI 66-80 ml) preoperatively to 63 ml (95% CI 54-72 ml) postoperatively (p < 0.001). The Evans index was 0.365 (95% CI 0.35-0.38) preoperatively and 0.358 (95% CI 0.34-0.38) postoperatively (p < 0.05). Postoperative change of CA showed a negative correlation with change of ventricular volume (r = -0.76, p < 0.01). CONCLUSIONS In this sample of patients with iNPH, the CA increased and ventricular volume decreased after shunt surgery. The relative difference was most pronounced for the CA, indicating that this accessible, noninvasive radiological marker should be evaluated further as an indirect method to determine shunt function in patients with iNPH.
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http://dx.doi.org/10.3171/2017.8.JNS17547DOI Listing
February 2018

Atypical anorexia nervosa is not related to brain structural changes in newly diagnosed adolescent patients.

Int J Eat Disord 2018 01 7;51(1):39-45. Epub 2017 Dec 7.

Department of Neuroscience, Functional Pharmacology Uppsala University, Uppsala, Sweden.

Objective: Patients with atypical anorexia nervosa (AN) have many features overlapping with AN in terms of genetic risk, age of onset, psychopathology and prognosis of outcome, although the weight loss may not be a core factor. While brain structural alterations have been reported in AN, there are currently no data regarding atypical AN patients.

Method: We investigated brain structure through a voxel-based morphometry analysis in 22 adolescent females newly-diagnosed with atypical AN, and 38 age- and sex-matched healthy controls (HC). ED-related psychopathology, impulsiveness and obsessive-compulsive traits were assessed with the Eating Disorder Examination Questionnaire (EDE-Q), Barratt Impulsiveness Scale (BIS-11) and Obsessive-compulsive Inventory Revised (OCI-R), respectively. Body mass index (BMI) was also calculated.

Results: Patients and HC differed significantly on BMI (p < .002), EDE-Q total score (p < .000) and OCI-R total score (p < .000). No differences could be detected in grey matter (GM) regional volume between groups.

Discussion: The ED-related cognitions in atypical AN patients would suggest that atypical AN and AN could be part of the same spectrum of restrictive-ED. However, contrary to previous reports in AN, our atypical AN patients did not show any GM volume reduction. The different degree of weight loss might play a role in determining such discrepancy. Alternatively, the preservation of GM volume might indeed differentiate atypical AN from AN.
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http://dx.doi.org/10.1002/eat.22805DOI Listing
January 2018

Structural whole-brain covariance of the anterior and posterior hippocampus: Associations with age and memory.

Hippocampus 2018 02 4;28(2):151-163. Epub 2017 Dec 4.

Department of Psychology, Uppsala University, Uppsala, Sweden.

The hippocampus (HC) interacts with distributed brain regions to support memory and shows significant volume reductions in aging, but little is known about age effects on hippocampal whole-brain structural covariance. It is also unclear whether the anterior and posterior HC show similar or distinct patterns of whole-brain covariance and to what extent these are related to memory functions organized along the hippocampal longitudinal axis. Using the multivariate approach partial least squares, we assessed structural whole-brain covariance of the HC in addition to regional volume, in young, middle-aged and older adults (n = 221), and assessed associations with episodic and spatial memory. Based on findings of sex differences in both memory and brain aging, we further considered sex as a potential modulating factor of age effects. There were two main covariance patterns: one capturing common anterior and posterior covariance, and one differentiating the two regions by capturing anterior-specific covariance only. These patterns were differentially related to associative memory while unrelated to measures of single-item memory and spatial memory. Although patterns were qualitatively comparable across age groups, participants' expression of both patterns decreased with age, independently of sex. The results suggest that the organization of hippocampal structural whole-brain covariance remains stable across age, but that the integrity of these networks decreases as the brain undergoes age-related alterations.
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http://dx.doi.org/10.1002/hipo.22817DOI Listing
February 2018

Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial.

EBioMedicine 2017 Oct 27;24:179-188. Epub 2017 Sep 27.

Department of Psychology, Uppsala University, Uppsala, Sweden.

Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).

Methods: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.

Findings: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n=24) as compared to covert (n=22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p<0.0001) with more than three times higher response rate (50% vs. 14%; χ(1)=6.91, p=0.009) and twice the effect size (d=2.24 vs. d=1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p≤0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p=0.0006) and attenuated amygdala (z threshold 2.70, p=0.003) activity.

Interpretation: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.

Funding Resources: The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).
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http://dx.doi.org/10.1016/j.ebiom.2017.09.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652281PMC
October 2017

Overview of neuroradiology.

Handb Clin Neurol 2017 ;145:579-599

Section of Neuroradiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Neuroradiology with computed tomography (CT) and magnetic resonance imaging (MRI) is essential for the initial evaluation of patients with a clinical suspicion of brain and spine disorders. Morphologic imaging is required to obtain a probable diagnosis to support the treatment decisions in pre- and perinatal disorders, vascular diseases, traumatic injuries, metabolic disorders, epilepsy, infection/inflammation, neurodegenerative disorders, degenerative spinal disease, and tumors of the central nervous system. Different postprocessing tools are increasingly used for three-dimensional visualization and quantification of lesions. Additional information is provided by angiographic methods and physiologic CT and MRI techniques, such as diffusion MRI, perfusion CT/MRI, MR spectroscopy, functional MRI, tractography, and nuclear medicine imaging methods. Positron emission tomography (PET) is now integrated with CT (PET/CT), and PET/MR scanners have recently also been introduced. These hybrid techniques facilitate the co-registration of lesions with different modalities, and give new possibilites for functional imaging. Repeated imaging is increasingly performed for treatment monitoring. The improved imaging techniques together with the neuropathologic diagnosis after biopsy or surgery allow more personalized treatment of the patient. Neuroradiology also includes endovascular treatment of aneurysms and arteriovenous malformations as well as thrombectomy in acute stroke. This catheter-based treatment has replaced invasive neurosurgery in many cases.
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http://dx.doi.org/10.1016/B978-0-12-802395-2.00037-7DOI Listing
January 2018

Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study.

Brain Res 2017 Nov 9;1675:102-115. Epub 2017 Sep 9.

Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden.

The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions.
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http://dx.doi.org/10.1016/j.brainres.2017.09.005DOI Listing
November 2017
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