15th European Molecular Imaging Meeting
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Disease Models for Translational Neuroimaging

Session chair: Andreas Hess (Nürnberg, Germany); Sebastien Coulliard-Despres (Salzburg, Austria)
 
Shortcut: PS 19
Date: Thursday, 27 August, 2020, 12:00 p.m. - 1:30 p.m.
Session type: Parallel Session

Contents

Abstract/Video opens by clicking at the talk title.

12:00 p.m. PS 19-01

Introductory Lecture

Sylvie Chalon1

1 Université de Tours, Tours, France

 
12:18 p.m. PS 19-02

Remote ischemic conditioning in a rat model of acute ischemic stroke: a two-center study with translational longitudinal MRI

Maryna Basalay1, Marlene Wiart2, Fabien Chauveau3, Chloe Dumot2, Christelle Leon2, Camille Amaz4, Radu Bolbos5, Diana Cash6, Eugene Kim6, Laura Mechtouff7, Tae-Hee Cho7, Norbert Nighoghossian7, Sean Davidson1, Michel Ovize2, Derek Yellon1

1 The Hatter Cardiovascular Institute, University College London, London, United Kingdom
2 Univ Lyon, CarMeN Inserm U1060, Lyon, France
3 Université Lyon, Lyon Neuroscience Research Center, CNRS UMR5292, Inserm U1028, Université Claude Bernard Lyon 1, Lyon, France
4 Clinical Investigation Center, CIC 1407, HCL, Louis Pradel Hospital, Lyon, France
5 CERMEP, Lyon, France
6 Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, France
7 Stroke department, Université Claude Bernard Lyon 1, CREATIS CNRS UMR 5220-INSERM U1206, INSA-Lyon; Hospices Civils de Lyon, Lyon, Germany

Introduction

Reperfusion is the only treatment for ischemic stroke patients; however, reperfusion may cause secondary brain damage. One of the feasible therapies targeting reperfusion injury is remote ischemic conditioning (RIC), a therapeutic approach whereby the application of brief episodes of ischemia/reperfusion to a tissue (e.g. the limb) can significantly protect a remote organ (e.g. the brain) [1]. The main objective of this study was to test the neuroprotective effects of RIC in a rat model of acute ischemic stroke in a two-center international study, using translational MR imaging endpoints.

Methods

The study was approved by our 2 local ethical committees, randomized and blinded, with a priori sample size calculation. Fig 1A shows the protocol. Eighty male Sprague Dawley rats underwent 90-min middle cerebral artery occlusion. Multiparametric MRI was performed per-occlusion to ascertain focal brain ischemia (inclusion criteria) and to control interindividual variability in the analysis. RIC was started 10 min before reperfusion, and consisted of 4 cycles of 5-min left hind limb ischemia. The primary endpoint of the study was infarct size measured on T2-weighted MRI at 24h, corrected for edema [2], and expressed as percentage of the area-at-risk of infarction. Secondary endpoints were space-modifying edema, infarct growth between per-occlusion and 24h MRI, and neurofunctional outcome.

Results/Discussion

Two animals died in each treatment group. In total, 47 animals were included in the analysis after applying pre-defined exclusion criteria (N=23 control and N=24 RIC) (Fig 1B). Fig 2A presents results for the overall population. Infarct size was significantly reduced in the RIC group. This infarct-limiting effect was still statistically significant after adjustment for pre-treatment apparent diffusion coefficient (ADC) lesion in multivariate analysis. In line with this result, RIC significantly improved neuroscores. The other secondary endpoints were not statistically different between groups. There was an excellent correlation between infarct size measured by MRI and that measured by TTC staining (0.87). To evaluate the effect of treatment in the most severely injured animals, we performed a subgroup analysis by including only the rats with ADC lesions > 100 mm3 (Fig 2B). For this cohort, both infarct size and neuroscores were significantly reduced in the RIC group.

Conclusions

RIC in the setting of acute stroke in rats is safe, reduces infarct size and improves functional recovery in a two-center international study. The use of longitudinal MRI increases the robustness of pre-clinical collaborative studies by: (i) the rigorous inclusion of animals, (ii) the possibility to adjust outcome with baseline (pre-treatment) data, (iii) the correction of edema in-vivo, and (iv) the use of translational imaging endpoints.

AcknowledgmentThe authors thank Jean-Baptiste Langlois of the Animage platform (CERMEP, Lyon) for his technical assistance. This study was supported by the Hatter Foundation and the National Institute for Health Research Biomedical Research Centre (NIHR-BRC) (BRC233/CM/SD/101320) and performed within the framework of the RHU MARVELOUS (ANR-16-RHUS-0009) of University Claude Bernard Lyon 1 (UCBL), within the program “Investissements d'Avenir”.
 
References
[1] Hess, D.C., et al., Remote ischaemic conditioning-a new paradigm of self-protection in the brain. Nat Rev Neurol, 2015. 11(12):698-710.
[2] Koch, S., et al., Atlas registration for edema-corrected MRI lesion volume in mouse stroke models. J Cereb Blood Flow Metab, 2019. 39(2):313-323.
Figure 1- Overview of experimental design (A) and CONSORT-like chart (B).
tMCAO: transient middle cerebral artery occlusion; PWI: perfusion-weighted MRI; MRA: magnetic resonance angiography; DWI: diffusion-weighted MRI; ADC: apparent diffusion coefficient; T2WI: T2-weighted MRI; RIC: remote ischemic conditioning; IS: infarct size; AAR: area at risk; Lvu: lesion volume uncorrected. CONSORT = Consolidated Standards of Reporting Trials.
Figure 2 Baseline data and efficacy outcome in overall population (A) and subgroup analysis (B).

Data are given as median [interquartile range]. Boxplots show the MRI primary endpoint; Graphs show the distribution of neuroscores (higher score indicates more disability). Subgroup analysis corresponds to rats with per-occlusion ADC lesion > 100 mm3, i.e. the most severely injured animals. *p<0.05, two-tailed Wilcoxon-Mann-Whitney tests except neuroscores: Fisher’s exact test. MRA: magnetic resonance angiography; ADC: apparent diffusion coefficient; AAR: area at risk; %HH: percentage of healthy hemisphere; IS: infarct size; HSE: hemispheric space-modifying oedema.

Keywords: Stroke, neuroprotection, MRI, remote ischemic conditioning, translational imaging
12:30 p.m. PS 19-03

Characterization of tissue evolution in a non-human primate (NHP) model of cerebral ischemia-reperfusion (CIR)

Justine Debatisse1, 2, Omer F. Eker3, 4, Océane Wateau5, Tae-Hee Cho1, 3, 4, Marlene Wiart1, Nicolas Costes6, Inés Mérida6, Christelle Léon1, Jean-Baptiste Langlois6, Thomas Troalen2, Christian Tourvieille6, Frédéric Bonnefoi6, Thibaut Iecker6, Didier Le Bars6, 4, Sophie Lancelot6, 4, Baptiste Bouchier4, Anne-Claire Lukasziewicz4, Norbert Nighoghossian1, 4, Michel Ovize1, 4, Hugues Contamin5, François Lux7, Olivier Tillement7, Emmanuelle Canet-Soulas1

1 Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Lyon, France
2 Siemens Healthcare SAS, Saint-Denis, France
3 CREATIS, CNRS UMR-5220, INSERM U1206, Université Lyon 1, INSA Lyon Bât. Blaise Pascal, Villeurbanne, France
4 Hospices Civils de Lyon, Lyon, France
5 Cynbiose SAS, Lyon, France
6 CERMEP - Imagerie du Vivant, Lyon, France
7 Institut Lumière Matière, CNRS UMR 5306, Université Claude Bernard Lyon 1, Lyon, France

Introduction

Early restoration of cerebral blood flow within ischemic tissue is a critical issue in the context of mechanical thrombectomy for large artery occlusion. New imaging biomarkers (PET-MRI) may characterize ischemic tissue evolution, blood-brain barrier (BBB) leakage (with nanoparticles AGuIX1) and microglial activity (with [11C]PK11195 PET), thus contributing to a better assessment of factors influencing salvageable penumbra2.

Methods

Study respected ARRIVE guidelines and was approved by ethical committees. Eleven Macaca fascicularis mature males underwent a 110-min transient minimally invasive endovascular MCA occlusion. We performed PET-MR imaging before intervention, per-ischemia, post-recanalization, after 7 and 30 days. We segmented per-ischemia diffusion weighted imaging, [15O]H2O-CBF maps and day 7 final infarct using FLAIR MRI. We derived 1) two evolutive tissue compartments, asymptomatic infarcted tissue (AIT) and symptomatic salvaged tissue (SST) (Fig.1A) and 2) in each compartment and respective mirror, values of apparent diffusion coefficient (ADC); Ktrans AGuIX reflecting BBB impairment and [11C]PK11195 binding. We expressed values as ipsilateral/contralateral ratios, compared using Wilcoxon test.

Results/Discussion

Illustrative maps of longitudinal PET-MRI imaging (Fig. 1B) show high early post-recanalization BBB permeability and marked later D7 [11C]PK11195 binding intensity and D30 extension.
We obtain a median final infarct of 2.74mL, SST of 3.55 mL, AIT of 0.53 mL representing 41% of the final infarct (Fig. 2A). Based on ratio analysis, we observe a significant ADC value decrease after recanalization in all compartments, even in AIT, “asymptomatic” in the acute phase and finally infarcting. ADC significantly increase after one week in all compartments (Fig.2B). High post-recanalization BBB leakage is present in several animals, but no significant differences were found, suggesting various evolution patterns (Fig.2C). [11C]PK11195 binding displays significant differences between basal state, D7 and D30 in both AIT and SST compartments (Fig.2D). The symptomatic tissue finally salvaged (SST) is significantly different from basal state when looking at ADC and microglial activity at late stages.

Conclusions

In a non-human primate model reproducing mechanical thrombectomy, we longitudinally characterized tissue evolution, in particular the SST compartment, which directly beneficiate from reperfusion. When looking at ADC (intracellular edema) and microglial activity, this tissue remains pathological at late stages of CIR (at least D7 after CIR). Clustering could identify evolution patterns that could be associated with functional outcomes.

AcknowledgmentThis work was supported by the RHU MARVELOUS (ANR-16-RHUS-0009) of l’Université Claude Bernard Lyon 1 (UCBL), within the program "Investissements d’Avenir“ operated by the French National Research Agency (ANR).
References
[1] Lux, F., Tran, V. L., Thomas, E. & Dufort, S. AGuIX ® from bench to bedside — Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine. 1–19 (2018).
[2] Baron, J. C. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nat. Rev. Neurol. 14, 325–337 (2018).
Figure 1

(A) Post-processing steps to identify the two evolution compartments: asymptomatic infarcted tissue and salvaged sympatomatic tissue. Hypoperfusion was defined as [15O2]H2O PET-CBF<0.2 mL/g/min.

(B) Illustrative maps of longitudinal PET-MRI imaging where we observe high early post-recanalization BBB permeability as well as marked later D7 [11C]PK11195 binding intensity and extension

Figure 2

Day 7 FLAIR (final infarct), AIT and SST volumes (A). All data are represented as median (range) of the 11 animals.

Boxplot showing the time course of ADC (B), Ktrans AGuIX (C) and [11C]PK11195 binding (D) in the three compartments (final infarct, AIT and SST). Animals are represented with individual color dots. Wilcoxon test was done to compare time points with a significance defined as p-value<0.05 (*).

Keywords: Ischemia-reperfusion, stroke model, PET-MRI, thrombectomy
12:42 p.m. PS 19-04

Non-invasive multimodal imaging of CSF-1R mediated microglia depletion after experimental stroke

Cristina Barca1, 2, Claudia Foray1, 2, Lydia Wachsmuth3, Cornelius Faber3, Michael Schäfers1, 4, Brian West5, Andreas H. Jacobs1, 2, 6, Bastian Zinnhardt1, 2, 4

1 Westfälische Wilhelms University Münster, European Institute for Molecular Imaging, Münster, Germany
2 PET Imaging in Drug Design and Development, Münster, Germany
3 Universitätsklinikum Münster, Translational Research Imaging Center, Münster, Germany
4 Universitätsklinikum Münster, Münster, Department of Nuclear Medicine, Münster, Germany
5 Plexxikon, Berkeley, United States of America
6 Johanniter Hospital, Department of Geriatrics, Bonn, Germany

Introduction

Modulation of microglial activity through inhibition of the CSF-1 receptor (CSF-1R) prior to transient middle cerebral artery occlusion (tMCAo) has shown to worsen disease outcomes despite its observed anti-inflammatory effects 1,2. However, the therapy effects of chronic CSF-1R inhibition after stroke remain unknown 3–5.
The aim of this project is to non-invasively investigate the therapy effects of long-term CSF-1R inhibition on TSPO, inflammatory markers, CBF, cellular density and behaviour in a murine ischemic model using non-invasive in vivo multimodal imaging

Methods

A total of N=16 male C57BL/6 mice fed with either standard chow or a PLX5622 diet (CSF-1R inhibitor, 1200 ppm; Plexxikon, Berkeley, CA) was investigated after a 30 min tMCAo for 35 days (n=8/group). T2 (lesion)-, perfusion (CBF)-, and diffusion (cellular density)-weighted MR imaging were acquired at day 1, 3, 7, 14, 21 and 30. Combined [18F]DPA-714 (TSPO) PET-CT was acquired at day 7, 14, 21 and 30. Percentage of injected tracer dose (%ID/cc) and infarct-to-contralateral ratio were calculated. Behavioural tests (grip test, rotarod, open field, pole test) were performed prior and after ischemia. We investigated CSF-1R expression, immune cells (Iba1, GFAP, F4/80) and vasculature (endothelium) by ex vivo analysis. Levels of inflammatory markers (IL-1β, IL6, TNF-α mRNA) are still investigated.

Results/Discussion

Maximum [18F]DPA-714 (TSPO) uptake within the infarct was observed between day 14 and 21 post ischemia in control mice, while tracer uptake was significantly decreased at day 14 in PLX5622-treated mice (ANOVA, p < 0.01). Moreover, tracer uptake was significantly decreased in the contralateral striatum of treated mice compared to control mice (Figure 1).
Infarct-to-contralateral cerebral blood flow ratios were increased in PLX5622 treated mice compared to control mice at day 7, 14, 21 and 30 post ischemia (ANOVA, p<0.05), indicative of faster re-perfusion of the infarcted tissue.
PLX5622 treatment did not change ADC values over time.
PLX5622-treated mice showed lower levels of CSF1R in the infarcted hemisphere compared to control mice (ANOVA, p = 0.049), but similar levels of Iba1-positive cells (p<0.05) (Figure 2).
Behavioural tests showed enhanced forepaw strength in PLX5622 treated mice at day 14 post ischemia (ANOVA, p=0.026).

Conclusions

This study supports a potential efficacy of a long-term PLX5622 treatment after ischemia on global inflammation (TSPO) and perfusion using in vivo non-invasive molecular imaging. Changes in imaging biomarkers were correlated with improved functional parameters (strength). A chronic CSF-1R inhibition seems to improve stroke outcome and may represent a step forward into immunomodulatory therapies in the post-ischemic phase.

Acknowledgment

This work was supported by the Horizon2020 Programme under grant agreement n° 675417 (PET3D).

References
[1] Szalay, G. et al. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat. Commun. 7, 11499 (2016).

[2] Elmore, M. R. P. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).

[3] Rice, R. A. et al. Microglial repopulation resolves inflammation and promotes brain recovery after injury. Glia 65, 931–944 (2017).
[4] Jin, W. N. et al. Depletion of microglia exacerbates postischemic inflammation and brain injury. J. Cereb. Blood Flow Metab. 37, 2224–2236 (2017).
[5] Otxoa-de-Amezaga, A. et al. Microglial cell loss after ischemic stroke favors brain neutrophil accumulation. Acta Neuropathol. 137, 321–341 (2019).
PLX5622 therapy effects on TSPO-dependent neuroinflammation detected by [18F]DPA-714 PET imaging
(A) Representative [18F]DPA-714 PET-CT images  (%ID/cc) of control (upper row) and PLX5622 treated mice (lower row) for each imaging time point. (B) Quantification within stroke lesion: a significant therapy effect was observed at day 14 post ischemia (control: 2.04 ±0.25, PLX5622: 1.60 ± 0.29, ANOVA, p =0.006). (C) Quantification within the contralateral side: a significant decrease in tracer uptake was also observed in the contralateral striatum at day 14, 21 and 30 post ischemia, indicative of a global drug effect on TSPO levels in the unaffected hemisphere.
Treatment effects on CSF-1R and Iba-1 expression at day 35 post ischemia
(A) Therapy efficiency was confirmed by WB, indicated by a decreased expression of CSF-1R within the infarcted hemisphere of PLX5622 treated mice (red, PLX5622: 0.27 ± 0.06) compared to control mice (green, control: 0.41 ± 0.09, ANOVA, p< 0.05). (B) Interestingly, no significant difference was observed in Iba1-positive cells between groups in that same region at day 35. (C) Levels of Iba1-positive cells were also assessed by immunoreactivity at day 35 post ischemia
Keywords: CSF-1R, MRI, stroke, immunomodulation, [18F]DPA-714 PET
12:54 p.m. PS 19-05

Molecular imaging for monitoring acute and chronic effects of an anti-epileptogenic treatment combination

Bettina J. Wolf1, 2, Pablo Bascuñana1, Ina Jahreis1, Martin Meier3, Tobias L. Ross1, Frank M. Bengel1, Marion Bankstahl3, 2, Jens P. Bankstahl1

1 Hannover Medical School, Nuclear Medicine, Hannover, Germany
2 University of Veterinary Medicine, Pharmacology, Toxicology and Pharmacy, Hannover, Germany
3 Hannover Medical School, Laboratory Animal Science, Hannover, Germany

Introduction

Severe brain insults can initiate epilepsy development. Anti-epileptogenic treatments aim to interfere with the epileptogenic process and to attenuate disease development. Treatment combinations targeting different aspects of epileptogenesis such as neuronal hyper-excitability and neuroinflammation are promising to attenuate seizure burden and comorbidities. Here, we investigated whether non-invasive imaging is able to predict anti-epileptogenic effects of a combinatorial treatment using phenobarbital and minocycline.

Methods

After epileptogenesis induction by pilocarpine-mediated status epilepticus (SE), rats were treated for two weeks with vehicle, minocycline (50 mg/kg daily), phenobarbital (15 mg/kg twice daily) or both compounds. Treatment impact on brain edema and ventricle volume (T2 MRI ratio to pons; 2 days and 6 weeks post SE), neuroinflammation ([18F]GE180 PET volume of distribution VT; 2 weeks post SE) as well as brain metabolism ([18F]FDG PET uptake; 6 weeks post SE) was evaluated by atlas-based and/or voxel-based statistical parametric mapping (SPM) analysis. Furthermore, chronic seizure burden (video/EEG monitoring) as well as behavioral alterations (open field test, sucrose consumption test, hyper-excitability test, Morris water maze test) were assessed between week 10 and 21 post SE.

Results/Discussion

While phenobarbital significantly attenuated early brain edema (up to -22%; p=0.006), strongly decreased the inflammatory signal (up to -38%; p<0.001) and later also ameliorated glucose hypometabolism in hippocampus and piriform cortex (SPM analysis), minocycline alone failed to alter any investigated parameter. Furthermore, phenobarbital-treated animals showed less ventricle enlargement (-78%; p=0.002) and less impaired learning abilities in the Morris water maze test (-39%; p=0.007). The treatment combination only slightly reduced neuroinflammation but lowered brain hypometabolism to a greater extent than sole phenobarbital treatment. An impact on seizure burden was not detected in any of the drug-treated groups. Over all groups, chronic ventricle enlargement positively correlated with impaired glucose metabolism (r=0.61; p<0.001), and early edema formation negatively correlated with seizure outcome (r=-0.48; p=0.011).

Conclusions

Only phenobarbital alone impacted chronic comorbidity development, while in combination with minocycline these effects were not observed. Furthermore, this study demonstrates that synergistic and antagonistic treatment effects influencing epileptogenic processes can be monitored by multi-parameter molecular imaging. This approach will serve as a helpful tool to guide dosing protocols and drug selection in future preclinical and clinical studies.

Treatment responses evaluated by [18F]GE180 and [18F]FDG PET.

Coronal statistical parametric maps showing significant differences of rats treated with single or combinatorial drugs during status epilepticus (SE)-induced epileptogenesis compared to vehicle treated animals (t-test, p < 0.05, minimum cluster size of 100 voxels) of (A) volume of distribution maps (VT [ml/cc], calculated by voxel-wise Logan graphical analysis) of [18F]GE180 or (B) uptake images [%ID/g] of [18F]FDG PET scans. Hot scale bar indicates significantly increased voxels, and cold scale bar significantly decreased voxels.

Keywords: Epilepsy, [18F]GE180, MRI
1:06 p.m. PS 19-06

Susceptibility-weighted and phase MR imaging for detecting intracranial calcifications in the P301L mouse model of human tauopathy

Ruiqing Ni1, Yvette Zarb2, Gisela A. Kuhn3, Zsofia Kovacs1, Ralph Müller3, Yankey Yundung1, Roger Nitsch4, Luka Kulic4, Annika Keller2, Jan Klohs1

1 University of Zurich and ETH, Institute for Biomedical Engineering, Zurich, Switzerland
2 University of Zurich, Institute of Neuropathology, Zurich, Switzerland
3 ETH Zurich, Institute for Biomechanics, Zurich, Switzerland
4 University of Zurich, Institute for Regenerative Medicine, Schlieren, Switzerland

Introduction

Intracranial calcifications have a higher incidence in patients with neurodegenerative diseases such as Alzheimer’s disease and frontotemporal dementia compared to age-matched controls, and may be linked to neuropsychiatric symptoms. Computed tomography is traditionally used to detect intracranial calcifications. Here, we investigated and validated the use of susceptibility-weighted imaging (SWI) and phase MR imaging, two gradient recalled echo (GRE) post-processing techniques [1, 2], as radiation-free alternatives to detect calcifications in the P301L mouse model of human tauopathy.

Methods

Homozygote P301L mice and non-transgenic littermates of 3, 5, 9 and 18-25 months-of-age (n=10-11 per group) were investigated. GRE data (60 μm resolution) was acquired at 9.4T. In addition, micro-computed tomography (8 µm resolution) data were obtained. From the GRE data a two-dimensional Fourier transform was used to compute the magnitude images. A phase unwrapping Gaussian filter was used to remove slowly varying phase shifts. Phase masks were created by setting all positive phases to 1 and by scaling negative phases linearly between 0 and 1. These masks were multiplied four times with the corresponding magnitude image to create SW images [2]. Immunohistochemical staining against CD31 (vessels), osteocalcin (calcification), AT100 and 8 (tau) was performed.

Results/Discussion

Intracranial calcifications were observed in P301L mice as regional hypointensties in SW images, matching diamagnetic lesions in corresponding phase images (Figure 1A). No calcifications were seen on non-transgenic littermates. Calcifications were mainly observed in the hippocampus, caudate nucleus, cortex and thalamus. In comparison, a lower number of calcifications were found on micro-computed tomography sections. The hippocampal calcifications in P301L mice shown by SWI showed an increase with advancing age (Figure 1B) and tau (AT8) pathology upon immunohistochemical analysis. Immunochemical staining on brain sections demonstrated intraneuronal osteocalcin associated with tau deposits (AT8 and AT100) and extraneuronal osteocalcin associated with blood vessels in the hippocampus (Figure 1C). In contrast, osteocalcin colocalized with CD31 staining for vessel in the thalamus with absence of tau deposits, indicating ossified vessels.

Conclusions

In conclusion, we describe the occurrence of intracranial calcifications as a new phenotype of a murine model of tauopathy, which can serve as a model of the human disease conditions. SWI and phase MR imaging are sensitive to detect these calcifications. They might thus become an important diagnostic tool and alternative to computed tomography to detect such alterations in a variety of brain diseases.

Acknowledgment

JK received funding from the Swiss National Science Foundation (320030_179277), in the framework of ERA-NET NEURON (32NE30_173678/1), the Synapsis foundation and the Vontobel foundation. RN received funding from the University of Zurich Forschungskredit (Nr. FK-17-052), and Synapsis foundation career development award (2017 CDA-03).

References
[1] Klohs J, Deistung A, Schweser F, Grandjean J, Dominietto M, Waschkies C, Nitsch RM, Knuesel I, Reichenbach JR, Rudin M. Detection of cerebral microbleeds with quantitative susceptibility mapping in the ArcAbeta mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab. 2011;31(12):2282-2292.
 
[2] Zarb Y, Weber-Stadlbauer U, Kirschenbaum D, Kindler DR, Richetto J, Keller D, Rademakers R, Dickson DW, Pasch A, Byzova T, Nahar K, Voigt FF, Helmchen F, Boss A, Aguzzi A, Klohs J, Keller A. Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response. Brain. 2019;142(4):885-902.
Figure 1
Intracranial calcifications in P301L mice. (A) Representative SW images (SWI) showing suspected bilateral calcifications (red arrowheads) of an 18 months-old P301L mouse. Corresponding phase images reveal positive phase shifts, indicating the diamagnetic nature of the lesion. (B) Quantification of regional distribution of calcified deposits. (C) Osteocalcin (OCN) immunohistochemistry of brain sections confirmed presence of calcifications. Low-density calcifications co-localize with tau in the hippocampus, and with blood vessels in the thalamus.
Keywords: magnetic resonance imaging, susceptibility-weighted imaging, phase mapping, calcifications, tau