Intersectin deficiency impairs cortico-striatal neurotransmission and causes obsessive-compulsive behaviors in mice.

The generation of appropriate behavioral responses involves dedicated neuronal circuits. The cortico-striatal-thalamo-cortical loop is especially important for the expression of motor routines and habits. Defects in this circuitry are closely linked to obsessive stereotypic behaviors, hallmarks of neuropsychiatric diseases including autism spectrum disorders (ASDs) and obsessive-compulsive disorders (OCDs). However, our knowledge of the essential synaptic machinery required to maintain balanced neurotransmission and plasticity within the cortico-striatal circuitry remains fragmentary. Mutations in the large synaptic scaffold protein intersectin1 (ITSN1) have been identified in patients presenting with ASD symptoms including stereotypic behaviors, although a causal relationship between stereotypic behavior and intersectin function has not been established. We report here that deletion of the two closely related proteins ITSN1 and ITSN2 leads to severe ASD/OCD-like behavioral alterations and defective cortico-striatal neurotransmission in knockout (KO) mice. Cortico-striatal function was compromised at multiple levels in ITSN1/2-depleted animals. Morphological analyses showed that the striatum of intersectin KO mice is decreased in size. Striatal neurons exhibit reduced complexity and an underdeveloped dendritic spine architecture. These morphological abnormalities correlate with defects in cortico-striatal neurotransmission and plasticity as well as reduced N-methyl-D-aspartate (NMDA) receptor currents as a consequence of postsynaptic NMDA receptor depletion. Our findings unravel a physiological role of intersectin in cortico-striatal neurotransmission to counteract ASD/OCD. Moreover, we delineate a molecular pathomechanism for the neuropsychiatric symptoms of patients carrying intersectin mutations that correlates with the observation that NMDA receptor dysfunction is a recurrent feature in the development of ASD/OCD-like symptoms.

Cortical matrix remodeling as a hallmark of relapsing-remitting neuroinflammation in MR elastography and quantitative MRI.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that involves both white and gray matter. Although gray matter damage is a major contributor to disability in MS patients, conventional clinical magnetic resonance imaging (MRI) fails to accurately detect gray matter pathology and establish a clear correlation with clinical symptoms. Using magnetic resonance elastography (MRE), we previously reported global brain softening in MS and experimental autoimmune encephalomyelitis (EAE). However, it needs to be established if changes of the spatiotemporal patterns of brain tissue mechanics constitute a marker of neuroinflammation. Here, we use advanced multifrequency MRE with tomoelastography postprocessing to investigate longitudinal and regional inflammation-induced tissue changes in EAE and in a small group of MS patients. Surprisingly, we found reversible softening in synchrony with the EAE disease course predominantly in the cortex of the mouse brain. This cortical softening was associated neither with a shift of tissue water compartments as quantified by T2-mapping and diffusion-weighted MRI, nor with leukocyte infiltration as seen by histopathology. Instead, cortical softening correlated with transient structural remodeling of perineuronal nets (PNNs), which involved abnormal chondroitin sulfate expression and microgliosis. These mechanisms also appear to be critical in humans with MS, where tomoelastography for the first time demonstrated marked cortical softening. Taken together, our study shows that neuroinflammation (i) critically affects the integrity of PNNs in cortical brain tissue, in a reversible process that correlates with disease disability in EAE, (ii) reduces the mechanical integrity of brain tissue rather than leading to water accumulation, and (iii) shows similar spatial patterns in humans and mice. These results raise the prospect of leveraging MRE and quantitative MRI for MS staging and monitoring treatment in affected patients.

Impaired functional connectivity of the hippocampus in translational murine models of NMDA-receptor antibody associated neuropsychiatric pathology.

Decreased hippocampal connectivity and disruption of functional networks are established resting-state functional MRI (rs-fMRI) features that are associated with neuropsychiatric symptom severity in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, the underlying pathophysiology of NMDAR encephalitis remains poorly understood. Application of patient-derived monoclonal antibodies against the NR1 (GluN1) subunit of the NMDAR now allows for the translational investigation of functional connectivity in experimental murine NMDAR antibody disease models with neurodevelopmental disorders. Using rs-fMRI, we studied functional connectivity alterations in (1) adult C57BL/6 J mice that were intrathecally injected with a recombinant human NR1 antibody over 14 days (n = 10) and in (2) a newly established mouse model with in utero exposure to a human recombinant NR1 antibody (NR1-offspring) at the age of (2a) 8 weeks (n = 15) and (2b) 10 months (n = 14). Adult NR1-antibody injected mice showed impaired functional connectivity within the left hippocampus compared to controls, resembling impaired connectivity patterns observed in human NMDAR encephalitis patients. Similarly, NR1-offspring showed significantly reduced functional connectivity in the hippocampus after 8 weeks, and impaired connectivity in the hippocampus was likewise observed in NR1-offspring at the age of 10 months. We successfully reproduced functional connectivity changes within the hippocampus in different experimental murine systems that were previously observed in human NMDAR encephalitis patients. Translational application of this method within a combined imaging and histopathological framework will allow future experimental studies to identify the underlying biological mechanisms and may eventually facilitate non-invasive monitoring of disease activity and treatment responses in autoimmune encephalitis.

Prediction of Stroke Outcome in Mice Based on Noninvasive MRI and Behavioral Testing.

BACKGROUND: Prediction of poststroke outcome using the degree of subacute deficit or magnetic resonance imaging is well studied in humans. While mice are the most commonly used animals in preclinical stroke research, systematic analysis of outcome predictors is lacking. METHODS: We intended to incorporate heterogeneity into our retrospective study to broaden the applicability of our findings and prediction tools. We therefore analyzed the effect of 30, 45, and 60 minutes of arterial occlusion on the variance of stroke volumes. Next, we built a heterogeneous cohort of 215 mice using data from 15 studies that included 45 minutes of middle cerebral artery occlusion and various genotypes. Motor function was measured using a modified protocol for the staircase test of skilled reaching. Phases of subacute and residual deficit were defined. Magnetic resonance images of stroke lesions were coregistered on the Allen Mouse Brain Atlas to characterize stroke topology. Different random forest prediction models that either used motor-functional deficit or imaging parameters were generated for the subacute and residual deficits. RESULTS: Variance of stroke volumes was increased by 45 minutes of arterial occlusion compared with 60 minutes. The inclusion of various genotypes enhanced heterogeneity further. We detected both a subacute and residual motor-functional deficit after stroke in mice and different recovery trajectories could be observed. In mice with small cortical lesions, lesion volume was the best predictor of the subacute deficit. The residual deficit could be predicted most accurately by the degree of the subacute deficit. When using imaging parameters for the prediction of the residual deficit, including information about the lesion topology increased prediction accuracy. A subset of anatomic regions within the ischemic lesion had particular impact on the prediction of long-term outcomes. Prediction accuracy depended on the degree of functional impairment. CONCLUSIONS: For the first time, we developed and validated a robust tool for the prediction of functional outcomes after experimental stroke in mice using a large and genetically heterogeneous cohort. These results are discussed in light of study design and imaging limitations. In the future, using outcome prediction can improve the design of preclinical studies and guide intervention decisions.

Myeloid cell subpopulations compensate each other for Ccr2-deficiency in glioblastoma.

AIMS: Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be facilitated by CCR2/CCL2 signalling. Besides the well-known CCR2+ macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2-deficiency of one of the myeloid cell populations affects the other population and tumour biology. METHODS: We generated four chimeric groups to analyse single and combined Ccr2-deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real-time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow-derived macrophages. RESULTS: We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2-knockout. Both microglia and macrophages with Ccr2-deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2-deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2-deficient microglia, whereas vessel stability was increased in mice with Ccr2-knockout in both cell populations. CONCLUSION: These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration.

Second hepatitis C virus transmission by blood components since introduction of mandatory NAT screening in Germany.

BACKGROUND: Viral safety of blood products in Germany has improved significantly over the last two decades. We describe the second documented transfusion-transmitted (TT) episode for the hepatitis C virus (HCV) in Germany since mandatory nucleic acid amplification techniques (NAT) screening was introduced in 1999. STUDY DESIGN AND METHODS: When a repeat donor who had tested negative for anti-HCV tested positive for HCV RNA by NAT in a minipool (MP) of eight, a look-back procedure was initiated. Qualitative, quantitative and genotyping assays were used to investigate the titers of the quarantined fresh frozen plasma (FFP) from the donor and a serum sample from the recipient of the pooled platelet concentrate (PPC). Amplified products of 5'UTR and HVR1 were used for sequence comparison to characterize the HCV genomic identity of donor and recipient samples. RESULTS: All NAT tests utilized in this procedure were able to detect a low HCV RNA titer (~15 IU/ml) in the FFP from the donation. Dilution of FFP by factor 8 was performed to mimic an MP, and the detection rate correlated well with the claimed sensitivity of the tests. Analysis of donor and recipient samples revealed genotype 3a viral transmission confirmed by sequence analysis. CONCLUSION: This TT HCV case could have been prevented by individual donation (ID) NAT. However, a low titer blood donation in the window period (WP) is very rare. Residual risk calculation for TT HCV in the WP revealed that, compared to MP-NAT testing, ID-NAT would improve blood safety only marginally.

Seasonal plasticity in the adult somatosensory cortex.

Seasonal cycles govern life on earth, from setting the time for the mating season to influencing migrations and governing physiological conditions like hibernation. The effect of such changing conditions on behavior is well-appreciated, but their impact on the brain remains virtually unknown. We investigate long-term seasonal changes in the mammalian brain, known as Dehnel's effect, where animals exhibit plasticity in body and brain sizes to counter metabolic demands in winter. We find large seasonal variation in cellular architecture and neuronal activity in the smallest terrestrial mammal, the Etruscan shrew, Suncus etruscus Their brain, and specifically their neocortex, shrinks in winter. Shrews are tactile hunters, and information from whiskers first reaches the somatosensory cortex layer 4, which exhibits a reduced width (-28%) in winter. Layer 4 width (+29%) and neuron number (+42%) increase the following summer. Activity patterns in the somatosensory cortex show a prominent reduction of touch-suppressed neurons in layer 4 (-55%), the most metabolically active layer. Loss of inhibitory gating occurs with a reduction in parvalbumin-positive interneurons, one of the most active neuronal subtypes and the main regulators of inhibition in layer 4. Thus, a reduction in neurons in layer 4 and particularly parvalbumin-positive interneurons may incur direct metabolic benefits. However, changes in cortical balance can also affect the threshold for detecting sensory stimuli and impact prey choice, as observed in wild shrews. Thus, seasonal neural adaptation can offer synergistic metabolic and behavioral benefits to the organism and offer insights on how neural systems show adaptive plasticity in response to ecological demands.

Long-Term Connectome Analysis Reveals Reshaping of Visual, Spatial Networks in a Model With Vascular Dementia Features.

BACKGROUND: Connectome analysis of neuroimaging data is a rapidly expanding field that offers the potential to diagnose, characterize, and predict neurological disease. Animal models provide insight into biological mechanisms that underpin disease, but connectivity approaches are currently lagging in the rodent. METHODS: We present a pipeline adapted for structural and functional connectivity analysis of the mouse brain, and we tested it in a mouse model of vascular dementia. RESULTS: We observed lacunar infarctions, microbleeds, and progressive white matter change across 6 months. For the first time, we report that default mode network activity is disrupted in the mouse model. We also identified specific functional circuitry that was vulnerable to vascular stress, including perturbations in a sensorimotor, visual resting state network that were accompanied by deficits in visual and spatial memory tasks. CONCLUSIONS: These findings advance our understanding of the mouse connectome and provide insight into how it can be altered by vascular insufficiency.

The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly, and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b and show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning, altered social interactions, and repetitive behaviors. We further demonstrate that Ube3b ubiquitinates the catalytic γ-subunit of calcineurin, Ppp3cc, the overexpression of which phenocopies Ube3b loss with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetically engineered mouse model.

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

The gray matter structural connectome and its relationship to alcohol relapse: Reconnecting for recovery.

Gray matter (GM) atrophy associated with alcohol use disorders (AUD) affects predominantly the frontal lobes. Less is known how frontal lobe GM loss affects GM loss in other regions and how it influences drinking behavior or relapse after treatment. The profile similarity index (PSI) combined with graph analysis allows to assess how GM loss in one region affects GM loss in regions connected to it, ie, GM connectivity. The PSI was used to describe the pattern of GM connectivity in 21 light drinkers (LDs) and in 54 individuals with AUD (ALC) early in abstinence. Effects of abstinence and relapse were determined in a subgroup of 36 participants after 3 months. Compared with LD, GM losses within the extended brain reward system (eBRS) at 1-month abstinence were similar between abstainers (ABST) and relapsers (REL), but REL had also GM losses outside the eBRS. Lower GM connectivities in ventro-striatal/hypothalamic and dorsolateral prefrontal regions and thalami were present in both ABST and REL. Between-networks connectivity loss of the eBRS in ABST was confined to prefrontal regions. About 3 months later, the GM volume and connectivity losses had resolved in ABST, and insula connectivity was increased compared with LD. GM losses and GM connectivity losses in REL were unchanged. Overall, prolonged abstinence was associated with a normalization of within-eBRS connectivity and a reconnection of eBRS structures with other networks. The re-formation of structural connectivities within and across networks appears critical for cognitive-behavioral functioning related to the capacity to maintain abstinence after outpatient treatment.

Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy.

Tumor recurrence is the main challenge in glioblastoma (GBM) treatment. Gold standard therapy temozolomide (TMZ) is known to induce upregulation of IL8/CXCL2/CXCR2 signaling that promotes tumor progression and angiogenesis. Our aim was to verify the alterations on this signaling pathway in human GBM recurrence and to investigate the impact of TMZ in particular. Furthermore, a combi-therapy of TMZ and CXCR2 antagonization was established to assess the efficacy and tolerability. First, we analyzed 76 matched primary and recurrent GBM samples with regard to various histological aspects with a focus on the role of TMZ treatment and the assessment of predictors of overall survival (OS). Second, the combi-therapy with TMZ and CXCR2-antagonization was evaluated in a syngeneic mouse tumor model with in-depth immunohistological investigations and subsequent gene expression analyses. We observed a significantly decreased infiltration of tumor-associated microglia/macrophages (TAM) in recurrent tumors, while a high TAM infiltration in primary tumors was associated with a reduced OS. Additionally, more patients expressed IL8 in recurrent tumors and TMZ therapy maintained CXCL2 expression. In mice, enhanced anti-tumoral effects were observed after combi-therapy. In conclusion, high TAM infiltration predicts a survival disadvantage, supporting findings of the tumor-promoting phenotype of TAMs. Furthermore, the combination therapy seemed to be promising to overcome CXCR2-mediated resistance.

SorCS2 facilitates release of endostatin from astrocytes and controls post-stroke angiogenesis.

SorCS2 is an intracellular sorting receptor of the VPS10P domain receptor gene family recently implicated in oxidative stress response. Here, we interrogated the relevance of stress-related activities of SorCS2 in the brain by exploring its role in ischemic stroke in mouse models and in patients. Although primarily seen in neurons in the healthy brain, expression of SorCS2 was massively induced in astrocytes surrounding the ischemic core in mice following stroke. Post-stroke induction was likely a result of increased levels of transforming growth factor ß1 in damaged brain tissue, inducing Sorcs2 gene transcription in astrocytes but not neurons. Induced astrocytic expression of SorCS2 was also seen in stroke patients, substantiating the clinical relevance of this observation. In astrocytes in vitro and in the mouse brain in vivo, SorCS2 specifically controlled release of endostatin, a factor linked to post-stroke angiogenesis. The ability of astrocytes to release endostatin acutely after stroke was lost in mice deficient for SorCS2, resulting in a blunted endostatin response which coincided with impaired vascularization of the ischemic brain. Our findings identified activated astrocytes as a source for endostatin in modulation of post-stroke angiogenesis, and the importance of the sorting receptor SorCS2 in this brain stress response.

Mapping internal brainstem structures using MP2RAGE derived T1 weighted and T1 relaxation images at 3 and 7 T.

The brainstem is a site of early pathology in several neurodegenerative diseases. The overall goal of this project was (a) To develop a method to segment internal brainstem structures from MP2RAGE derived images. (b) To compare the segmentations at 3 and 7 T. (c) To investigate age effects on intensities and segmentations. MP2RAGE derived T1 weighted images (UNI) and T1 relaxation maps (T1map) were obtained from two public data sets (LEMON: 50 3 T data sets, ATAG: 46 7 T data sets). The UNI and T1map images were rescaled using a linear scaling procedure and a ratio (RATIO) image calculated. The brainstem was extracted and k-mean clustering used to identify six intensity clusters from the UNI, T1map and RATIO at 3 and 7 T. Nonlinear diffeomorphic mapping was used to warp the six intensity clusters in subject space into a common space to generate probabilistic group averages/priors that were used to inform the final probabilistic segmentations at the single subject level for each field strength. The six clusters corresponded to six brainstem tissue types (three gray matter clusters and two white matter clusters and one csf/tissue boundary cluster). The quantitative comparison of the 3 and 7 T probabilistic averages showed subtle differences that affected the localization of age-associated brainstem volume losses. The segmentation approach presented here identified the same brainstem gray and white matter structures at both field strengths. Further studies are necessary to investigate how resolution and field strength contribute to the subtle differences observed at the two field strengths.

Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function.

OBJECTIVE: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. METHODS: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240µg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. RESULTS: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. INTERPRETATION: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.

Longitudinal 19F magnetic resonance imaging of brain oxygenation in a mouse model of vascular cognitive impairment using a cryogenic radiofrequency coil.

INTRODUCTION: We explored the use of a perfluoro-15-crown-5 ether nanoemulsion (PFC) for measuring tissue oxygenation using a mouse model of vascular cognitive impairment. METHODS: Seventeen C57BL/6 mice underwent stereotactic injection of PFC coupled to a fluorophore into the striatum and corpus callosum. Combined 1H/19F magnetic resonance imaging (MRI) to localize the PFC and R1 mapping to assess pO2 were performed. The effect of gas challenges on measured R1 was investigated. All mice then underwent bilateral implantation of microcoils around the common carotid arteries to induce global cerebral hypoperfusion. 19F-MRI and R1 mapping were performed 1 day, 1 week, and 4 weeks after microcoil implantation. In vivo R1 values were converted to pO2 through in vitro calibration. Tissue reaction to the PFC was assessed through ex vivo immunohistochemistry of microglial infiltration. RESULTS: R1 increased with increasing oxygen concentrations both in vitro and in vivo and the strength of the 19F signal remained largely stable over 4 weeks. In the two mice that received all four scans, tissue pO2 decreased after microcoil implantation and recovered 4 weeks later. We observed infiltration of the PFC deposits by microglia. DISCUSSION: Despite remaining technical challenges, intracerebrally injected PFC is suitable for monitoring brain oxygenation in vivo.

Quantitative surface analysis of combined MRI and PET enhances detection of focal cortical dysplasias.

OBJECTIVE: Focal cortical dysplasias (FCDs) often cause pharmacoresistant epilepsy, and surgical resection can lead to seizure-freedom. Magnetic resonance imaging (MRI) and positron emission tomography (PET) play complementary roles in FCD identification/localization; nevertheless, many FCDs are small or subtle, and difficult to find on routine radiological inspection. We aimed to automatically detect subtle or visually-unidentifiable FCDs by building a classifier based on an optimized cortical surface sampling of combined MRI and PET features. METHODS: Cortical surfaces of 28 patients with histopathologically-proven FCDs were extracted. Morphology and intensity-based features characterizing FCD lesions were calculated vertex-wise on each cortical surface, and fed to a 2-step (Support Vector Machine and patch-based) classifier. Classifier performance was assessed compared to manual lesion labels. RESULTS: Our classifier using combined feature selections from MRI and PET outperformed both quantitative MRI and multimodal visual analysis in FCD detection (93% vs 82% vs 68%). No false positives were identified in the controls, whereas 3.4% of the vertices outside FCD lesions were also classified to be lesional ("extralesional clusters"). Patients with type I or IIa FCDs displayed a higher prevalence of extralesional clusters at an intermediate distance to the FCD lesions compared to type IIb FCDs (p < 0.05). The former had a correspondingly lower chance of positive surgical outcome (71% vs 91%). CONCLUSIONS: Machine learning with multimodal feature sampling can improve FCD detection. The spread of extralesional clusters characterize different FCD subtypes, and may represent structurally or functionally abnormal tissue on a microscopic scale, with implications for surgical outcomes.

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Observations in witnessed Sudden Unexpected Death in Epilepsy (SUDEP) suggest that a fatal breakdown of the central autonomic control could play a major role in SUDEP. A previous MR study found volume losses in the mesencephalon in focal epilepsy that were more severe and extended into the lower brainstem in two patients who later died of SUDEP. The aims of this study were to demonstrate an association (1) between brainstem volume loss and impaired autonomic control (reduced heart rate variability [HRV]); (2) between brainstem damage and time to SUDEP in patients who later died of SUDEP. Two populations were studied: (1) Autonomic system function population (ASF, 18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3 T MR exams. (2) SUDEP population (26 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion indicating significant volume loss or atrophy. The total number of regions with excessive expansion in ASF was negatively correlated with HRV (r = -.37, p = .03), excessive volume loss in periaqueductal gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r2 = -.82/.67, p < .001). The total number of regions with excessive expansion in SUDEP was negatively correlated with time to SUDEP (r = -.39, p = .03), excessive volume loss in the raphe/medulla oblongata at the obex level explained most of the variation of the time between MRI to SUDEP (r/r2 = -.60/.35,p = .001). Epilepsy is associated with brainstem atrophy that impairs autonomic control and can increase the risk for SUDEP if it expands into the mesencephalon.

Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging.

Purpose To synthesize two low-molecular-weight iron chelates and compare their T1 contrast effects with those of a commercial gadolinium-based contrast agent for their applicability in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging. Materials and Methods The animal experiments were approved by the local ethics committee. Two previously described iron (Fe) chelates of pentetic acid (Fe-DTPA) and of trans-cyclohexane diamine tetraacetic acid (Fe-tCDTA) were synthesized with stability constants several orders of magnitude higher than those of gadolinium-based contrast agents. The T1 contrast effects of the two chelates were compared with those of gadopentetate dimeglumine in blood serum phantoms at 1.5 T, 3 T, and 7 T. For in vivo studies, a human breast cancer cell line (MDA-231) was implanted in five mice per group. The dynamic contrast effects of the chelates were compared by performing DCE MR imaging with intravenous application of Fe-DTPA or Fe-tCDTA on day 1 and DCE MR imaging in the same tumors with gadopentetate dimeglumine on day 2. Quantitative DCE maps were generated with software and were compared by means of a one-tailed Pearson correlation test. Results Relaxivities in serum (0.94 T at room temperature) of Fe-tCDTA (r1 = 2.2 mmol-1 · sec-1, r2 = 2.5 mmol-1 · sec-1) and Fe-DTPA (r1 = 0.9 mmol-1 · sec-1, r2 = 0.9 mmol-1 · sec-1) were approximately twofold and fivefold lower, respectively, compared with those of gadopentetate dimeglumine (r1 = 4.1 mmol-1 · sec-1, r2 = 4.8 mmol-1 · sec-1). Used at moderately higher concentrations, however, iron chelates generated similar contrast effects at T1-weighted MR imaging in vitro in serum, in vivo in blood, and for DCE MR imaging of breast cancer xenografts. The volume transfer constant values for Fe-DTPA and Fe-tCDTA in the same tumors correlated well with those observed for gadopentetate dimeglumine (Fe-tCDTA Pearson R, 0.99; P = .0003; Fe-DTPA Pearson R, 0.97; P = .003). Conclusion Iron-based contrast agents are promising as alternatives for contrast enhancement at T1-weighted MR imaging and have the potential to contribute to the safety of MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

Neuroimaging Biomarkers Predict Brain Structural Connectivity Change in a Mouse Model of Vascular Cognitive Impairment.

BACKGROUND AND PURPOSE: Chronic hypoperfusion in the mouse brain has been suggested to mimic aspects of vascular cognitive impairment, such as white matter damage. Although this model has attracted attention, our group has struggled to generate a reliable cognitive and pathological phenotype. This study aimed to identify neuroimaging biomarkers of brain pathology in aged, more severely hypoperfused mice. METHODS: We used magnetic resonance imaging to characterize brain degeneration in mice hypoperfused by refining the surgical procedure to use the smallest reported diameter microcoils (160 µm). RESULTS: Acute cerebral blood flow decreases were observed in the hypoperfused group that recovered over 1 month and coincided with arterial remodeling. Increasing hypoperfusion resulted in a reduction in spatial learning abilities in the water maze that has not been previously reported. We were unable to observe severe white matter damage with histology, but a novel approach to analyze diffusion tensor imaging data, graph theory, revealed substantial reorganization of the hypoperfused brain network. A logistic regression model from the data revealed that 3 network parameters were particularly efficient at predicting group membership (global and local efficiency and degrees), and clustering coefficient was correlated with performance in the water maze. CONCLUSIONS: Overall, these findings suggest that, despite the autoregulatory abilities of the mouse brain to compensate for a sudden decrease in blood flow, there is evidence of change in the brain networks that can be used as neuroimaging biomarkers to predict outcome.