Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling, human myelofibrosis

Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of Abi1 in a novel mouse model leads to development of an MPNlike phenotype resembling human PMF. Abi1 loss resulted in a significant increase in the activity of the Src family kinases (SFKs), STAT3, and NF-κB signaling. We also observed impairment of hematopoietic stem cell self-renewal and fitness, as evidenced in noncompetitive and competitive bone marrow transplant experiments. CD34 + hematopoietic progenitors and granulocytes from patients with PMF showed decreased levels of ABI1 transcript as well as increased activity of SFKs, STAT3, and NF-κB. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-κB signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF

An interpretable machine learning model to explain the interplay between brain lesions and cortical atrophy in multiple sclerosis

: Multiple Sclerosis (MS) is the most common cause, (after trauma) of neurological disability in young adults in Western countries. While several Magnetic Resonance Imaging (MRI) studies have demonstrated a strong association between the presence of cortical grey matter atrophy and the progression of neurological impairment in MS patients, the neurobiological substrates of cortical atrophy in MS, and in particular its relationship with white matter (WM) and cortical lesions, remain unknown. The aim of this study was to investigate the interplay between cortical atrophy and different types of lesions at Ultra-High Field (UHF) 7 T MRI, including cortical lesions and lesions with a susceptibility rim (a feature which histopathological studies have associated with impaired remyelination and progressive tissue destruction). We combined lesion characterization with a recent machine learning (ML) framework which includes explainability, and we were able to predict cortical atrophy in MS from a handful of lesion-related features extracted from 7 T MR imaging. This highlights not only the importance of UHF MRI for accurately evaluating intracortical and rim lesion load, but also the differential contributions that these types of lesions may bring to determine disease evolution and severity. Also, we found that a small subset of features [WM lesion volume (not considering rim lesions), patient age and WM lesion count (not considering rim lesions), intracortical lesion volume] carried most of the prediction power. Interestingly, an almost opposite pattern emerged when contrasting cortical with WM lesion load: WM lesion load is most important when it is small, whereas cortical lesion load behaves in the opposite way.Clinical Relevance- Our results suggest that disconnection and axonal degeneration due to WM lesions and local cortical demyelination are the main factors determining cortical thinning. These findings further elucidate the complexity of MS pathology across the whole brain and the need for both statistical and mechanistic approaches to understanding the etiopathogenesis of lesions

Precurved electrode array and insertion tool

This is a publisher’s version of an article published in Annals of Otology, Rhinology & Laryngology published by Annals Publishing Company. This version is reproduced with permission from Annals Publishing Company. http://www.annals.com/Future improvements in the performance of patients using cochlear implants largely depend on improving the electrode array design. In particular, it is necessary to produce an array that would lie in the desired portion of the scala tympani while minimizing insertion trauma to the cochlea

Whole brain in vivo axonal diameter mapping in multiple sclerosis

Traditional techniques based on diffusion MR imaging suffer from extremely low specificity in separating disease-related alterations in white matter microstructure, which can involve multiple phenomena including axonal loss, demyelination and changes in axonal size. Multi-shell diffusion MRI is able to greatly increase specificity by concomitantly exploring multiple diffusion timescales. If multi-shell acquisition is combined with an exploration of different diffusion times, diffusion data allows the estimation of sophisticated compartmental models, which provide greatly enhanced specificity to the presence of different tissue sub-compartments, as well as estimates of intra-voxel axonal diameter distributions. In this paper, we apply a multiple-b-value, high angular resolution multi-shell diffusion MRI protocol with varying diffusion times to a cohort of multiple sclerosis (MS) patients and compare them to a population of healthy controls. By fitting the AxCaliber model, we are able to extract indices for axonal diameter across the whole brain. We show that MS is associated with widespread increases of axonal diameter and that our axonal diameter estimation provides the highest discrimination power for local alterations in normal-appearing white matter in MS compared to controls. AxCaliber has the potential to disentangle microstructural alterations in MS and holds great promises to become a sensitive and specific non-invasive biomarker of irreversible disease progression

Thalamic atrophy and its substrates in multiple sclerosis by ultra-high field MRI

Introduction: Thalamic atrophy appears early in MS and serves as a biomarker for neurodegeneration. Some studies have linked MS thalamic atrophy to white matter lesion volume, but its relationship with local and cortical pathology was less investigated. Ultra-high field MRI demonstrates high sensitivity to cortical and thalamic lesions. Aim: We used 7T and 3T MRI to characterize the presence of lesional and neurodegenerative thalamic pathology in a heterogenous MS cohort. We further investigated the contribution of local and distant lesion pathology and cortical atrophy to thalamic atrophy. Methods: In 83 MS patients (57 RRMS, 26 SPMS) and 44 age-matched healthy controls, 7T T2*-weighted images were acquired for lesion segmentation, 3T T1-weighted scans for cortical thickness and thalamic volume estimation. Thalamic volume was normalized to total intracranial volume. Regression analysis was used to identify predictors of thalamic atrophy using age as a covariate. Results: 38/83 MS patients presented with thalamic lesions. Overall, normalized thalamic volume was smaller in patients relative to healthy controls (mean±SD = 3×10-3±5.7×10-4 mm3 vs. 3.4×10-3±5.1×10-4 mm3; p = 0.0002, by linear regression), including phenotypes (RRMS: 3.2×10-3±5.4×10-4 mm3; p = 0.017 vs. SPMS: 2.6×10-3±4.6×10-4 mm3; p < 0.0001, by linear regression). Thalamic volume, however, did not differ between groups of patients with or without thalamic lesions (p= 0.426). Regression analysis demonstrated that thalamic atrophy in MS patients was explained by white matter atrophy (p < 0.0001) and cortical thickness (p = 0.002) and unrelated to thalamic and cortical lesion load. Discussion: The data indicate that thalamic atrophy in MS is independent from local lesion pathology, and suggest that disconnection mechanisms, from white matter lesions and cortex, might play a greater role than local thalamic pathology in inducing thalamic atrophy in the disease

In vivo characterization of cerebellar microglia activation in multiple sclerosis by combined 11C-PBR28 MR-PET and 7 Tesla MRI.

Introduction Cerebellar involvement occurs early in multiple sclerosis (MS), and is associated with neurological impairment and disease progression. Neuropathological cerebellar examinations in MS reported heterogeneous processes including demyelination, neurodegeneration and microglia activation. The role of microglia in the pathogenesis of cerebellar pathology is unknown. Activated microglia upregulate expression of the 18kDa translocator protein (TSPO), which can be imaged in vivo using the 11C-PBR28 radioligand. Objectives We investigated, using integrated 3 Tesla (3T) magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, TSPO expression in lesional and non lesional white and grey matter (WM, GM) in the cerebellum of a heterogeneous MS cohort, and its association with cerebellar lesions, atrophy and clinical parameters. Cerebellar lesions were characterized using ultra high resolution 7 Tesla (7T) MRI. Methods Twenty-seven patients with MS (13 relapsing-remitting, RRMS, 14 secondary progressive, SPMS) and 18 healthy controls (HC) matched for age and PBR28 affinity, were included in the study. All subjects underwent 90-min 11C-PBR28 MR-PET. Anatomical 3T images of the cerebellum for regions of interest segmentation were also acquired. A manual segmentation was performed to extract whole cerebellum (WHC) masks on Freesurfer (Figure 1A). In patients, normal appearing WHC (NAWHC) was obtained by subtracting the lesion masks to the WHC mask using FSL. Cerebellar WM and GM were segmented using Volbrain (Figure 1B), and volumes were normalized by total intracranial volume in Freesurfer. In patients, cerebellar lesions were segmented on 7 T T1-weighted images (0.6x0.6x1.5 mm3) obtained on a separate session by using Slicer v 4.2 (Figure 2). Quantification of 11C-PBR28 uptake in the WHC, NAWHC, GM, WM and cerebellar lesions (CL) was performed using 60-90 minutes standardized uptake values normalized by a pseudoreference region in the normal appearing basal ganglia. Tracer uptake was extracted in cerebellar lesions that have been grouped according to localization in cortical (CCL), leukocortical (LCL), deep grey matter (DGML), and purely WM lesions (WML). All patients underwent neurological and cognitive assessment by Expanded Disability Status Scale (EDSS) and Symbol Digit Modality Test (SDMT). Linear regression models were used to compare cerebellar 11C-PBR28 uptake in MS patients versus controls, and to assess their relationship with EDSS. Age and binding affinity were included as covariates of no interest. Spearman correlation coefficient was used to assess the association between clinical parameters (EDSS, SDMT) and uptake values. Matched-pair T-test was performed to search for differences in lesion uptake between different regions of interest. Results Mean age for patients was 48±10, EDSS ranged from 1.5 to 7.5 (median 3.5, mean 4.0). Mean age for HC was 49±12. Cerebellar lesions were found in 13 out of 14 SPMS and in 10 out of 13 RRMS. In RRMS, most of the lesions are localized in the WM; in progressive patients, a majority of leucocortical lesions has been detected. No significant differences in the uptake were found in lesions affecting different regions in the cerebellum, when considering all patients as one group, and after separating SPMS and RRMS patients. Compared to controls, MS subjects showed significantly higher PBR28 uptake in all examined regions: WHC (p=0.04), NAWHC (p=0.05), GM (p=0.04), WM (p=0.03). Within patients, the mean uptake was higher in lesions then in the rest of the parenchyma (1.45 versus 1.39) though not significantly. There was a significative difference between global lesion uptake and the uptake in the cerebellum of HC (p=0.02, Figure 3D). No differences in uptake were found in SPMS versus RRMS. Tracer uptake in the WM correlated positively with EDSS (p=0.03), and negatively with SDMT z-scores (p<0.01). When corrected for age and tracer binding affinity, this significance became a trend for EDSS (p=0.07) but was maintained for SDMT (p=0.04), being the age a determinant for motor and cognitive performance reduction. There was no correlation between cerebellar volume, cerebellar lesion load and tracer uptake in any of the regions examined. Discussion Our data provide in vivo evidence for the presence of diffuse microglia activation in the cerebellum in MS. Interestingly, the highest increase in microglia activation was detected in lesions that were mainly concentrated in WM in RRMS, while they extensively involved the cortical cerebellar GM in SPMS. Abnormal microglia activation in the WM was related to worse neurological disability and cognitive performance in the whole MS cohort. Conclusions MR-PET is a valid tool to estimate cerebellar neuroinflammation in patients with MS. Future studies will assess its longitudinal evolution in relation to structural pathology and clinical outcome

Profiles of cortical and white matter lesion inflammation in multiple sclerosis by combined 11C-PBR28 and 7 T imaging

Background: Microglia accumulate in a cytotoxic phenotype in active demyelinating white matter lesions (WML), while drop in numbers and change to a homeostatic phenotype in inactive lesions. Whether this activity pattern can be detected in cortical lesions (CL), the relation between inflammation in CL and WML and their clinical correlates are unknown. Goals: To characterize in vivo, using 7 T and magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, which binds to activated microglia, profiles of inflammatory activity in CL and WML and their association with clinical burden. Methods: Eleven secondary-progressive, 11 relapsing-remitting multiple sclerosis (SPMS, RRMS) patients, and 14 age- and binding affinity matched healthy controls underwent MR-PET and 7T T2* imaging. 11C-PBR28 binding was measured using normalized standardized uptake values (SUVR) in WML and CL segmented at 7 T. The relative difference in cortical and WM SUVR between patients and controls was used to classify CL and WML as active or inactive. Active WML included lesions active only in the core, lesions active only perilesionally or both. The relationship between profiles of microglia activity in CL and WML within patients was studied using χ2-test. The median of active CL and WML was assessed in patients and used to classify each subject with high or low CL and WML inflammation respectively. Differences in Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) scores were investigated in patients with high versus low CL and WML inflammation using Mann-Whitney U-test. Results: In RRMMS, 30/103 (29%) CL and 80/412 (20%) WML, in SPMS 226/410 (55%) and 279/588 (47%) were identified as active. Six out of 22 patients showed different profiles of inflammation in CL and WML and the relation between inflammatory profiles in CL and WML showed only a trend (p = 0.08). Patients with high inflammatory CL activity had lower SDMT scores than patients with low CL inflammation (p=0.02). Patients with high inflammatory WML activity had also lower SDMT scores and higher EDSS than patients with low CL inflammation (p=0.05, p=0.002, respectively). Conclusions: 11C-PBR28 and 7 T imaging reveal distinct inflammatory profiles in CL and WML in MS, which can be used to identify patients with more aggressive disease. Inflammatory activity in CL is not strictly related to WML inflammation, suggesting distinct underlying microglia-mediated events

Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11 C-PBR28 MR-PET

Background: Activated microglia, which can be detected in vivo by 11 C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11 C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11 C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11 C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment