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1
Review
Front Immunol
. 2019 Jul 11;10:1564. doi: 10.3389/fimmu.2019.01564. eCollection 2019.
Immunological Aspects of Approved MS Therapeutics
Paulus S Rommer 1, Ron Milo 2 3, May H Han 4, Sammita Satyanarayan 4, Johann Sellner 5 6, Larissa Hauer 7, Zsolt Illes 8 9, Clemens Warnke 10, Sarah Laurent 10, Martin S Weber 11 12, Yinan Zhang 13, Olaf Stuve 6 13 14
Affiliations expand
PMID: 31354720
PMCID: PMC6637731
DOI: 10.3389/fimmu.2019.01564Free PMC article
Abstract
Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.
Keywords: immunomodulation; immunosuppression; immunotherapeutics; monoclonal antibodies; multiple sclerosis.
Cited by 10 articles
283 references
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2
Review
Neuropathology
. 2020 Feb;40(1):40-56. doi: 10.1111/neup.12606. Epub 2019 Dec 5.
Phenotypic variability and its pathological basis in amyotrophic lateral sclerosis
Takahiro Takeda 1 2, Kazuo Kitagawa 2, Kimihito Arai 1
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PMID: 31802540
DOI: 10.1111/neup.12606
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by its inherent clinicopathological variability. The concurrence of upper and lower motor neuron signs is a common feature in the majority of patients with ALS. However, some patients manifest an atypical clinical course, with only upper or lower motor neuron signs, or various extra-motor symptoms including cognitive dysfunction, parkinsonism, autonomic dysfunction, or ophthalmoparesis. This variability indicates different manifestations of ALS and is reflected by ALS pathology spreading into the central nervous system. The presence of cytoplasmic inclusions positive for transactivation response DNA-binding protein 43 kDa (TDP-43) is a key feature in ALS. Loss of TDP-43 from the nucleus and its subsequent aggregation in the cytoplasm may occur in susceptible regions and may be associated with neuronal loss. However, in some regions, there is no apparent neuronal loss while TDP-43 accumulation is evident; in contrast, in other regions, neuronal loss is apparent without any evidence of TDP-43 accumulation. Therefore, in addition to TDP-43 dysfunction, underlying region-specific cellular vulnerability may exist in the upper and lower motor neurons and frontotemporal system in patients with ALS. The microscopic discrepancy and selective vulnerability may be linked to the macroscopic propensities of the sites of onset, and may also determine the direction and rate of progression of the lesions. Thus, there may be multicentric sites of onset, region-oriented disease development, and different speeds of disease progression across patients with ALS. ALS lesions occur in motor-related areas but may spread to neighboring areas. However, since lesions may spread in a discontinuous manner, and the dynamics of disease propagation have not been able to be identified, it remains controversial whether the stepwise appearance of TDP-43-positive inclusions is based on direct cell-to-cell protein propagation. Further understanding of the phenotypic variability of ALS and its pathological basis may serve as a guide for investigating the underlying pathogenesis of ALS.
Keywords: Bunina body; Charcot; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration.
© 2019 Japanese Society of Neuropathology.
Cited by 2 articles
121 references
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3
Childs Nerv Syst
. 2019 Sep;35(9):1537-1545. doi: 10.1007/s00381-019-04222-z. Epub 2019 May 31.
H3K27M, IDH1, and ATRX expression in pediatric GBM and their clinical and prognostic significance
Alok Mohan Uppar 1, Harsha Sugur 2, A R Prabhuraj 1, M Bhaskara Rao 1, B Indira Devi 1, S Sampath 1, A Arivazhagan 3, Vani Santosh 2
Affiliations expand
PMID: 31152217
DOI: 10.1007/s00381-019-04222-z
Abstract
Purpose: Pediatric glioblastoma (pGBM) tumors have been identified as an entity distinct and different from the adult variety of GBM not only with respect to pathogenesis, genetics, and molecular alterations but also in clinical outcomes and overall survival. This study aims to evaluate the immunohistochemical profile of molecular markers in pediatric GBM and correlate them with clinical features and prognosis.
Materials and methods: We retrospectively analyzed 29 pGBMs (age range 3 to 18 years), operated at our institute between 2009 and 2014, and evaluated their clinical and histopathological features along with the immunohistochemical expression of clinically relevant molecular markers: H3K27M, p53, ATRX, and IDH1 (R132H), and correlated their expression with clinical features. We further assessed the prognostic value of these markers in our cohort of patients.
Results: The median overall survival (OS) of the cohort was 6.00 ± 0.882 months. The mean overall survival was 7.571 ± 1.118 months which was lower than in most studies. Preoperative Karnofsky Performance Score (KPS), extent of surgical resection, and adjuvant radiotherapy were found to be the clinical factors strongly influencing median survival (p < 0.05). Loss of ATRX expression was predominantly noted in hemispheric tumors (84%), while p53 staining was maximum in thalamic tumors (8 out of 9 cases). H3K27M mutant protein expression was noted in 8/9 thalamic tumors and 5/7 tumors in the brain stem-cerebellar-peduncular region. Patients with tumors showing H3K27M immunopositivity had the worst prognosis with a mean OS of 5 months ± 0.832 months, as against patients with H3K27M-immunonegative tumors, which was 10.143 ± 1.866 months(p = 0.006). Other markers like p53, ATRX, and IDH1 did not influence the prognosis in this patient cohort. ATRX loss of expression was associated with a better OS, with a trend to significance, and such an association has not been reported earlier.
Conclusions: Ours is one among the few studies from India describing the clinical parameters and evaluating the key immunohistochemical markers in pGBM and deriving their prognostic significance. The study reiterates the poor prognostic significance of H3K27M immunopositivity.
Keywords: ATRX; Glioblastoma; H3K27M; IDH1; Immunohistochemistry; Pediatric.
26 references
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4
Cell
. 2020 Mar 19;180(6):1067-1080.e16. doi: 10.1016/j.cell.2020.02.035. Epub 2020 Mar 10.
Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism
Alexander Duscha 1, Barbara Gisevius 1, Sarah Hirschberg 1, Nissan Yissachar 2, Gabriele I Stangl 3, Eva Eilers 4, Verian Bader 5, Stefanie Haase 6, Johannes Kaisler 1, Christina David 1, Ruth Schneider 1, Riccardo Troisi 1, Daniel Zent 1, Tobias Hegelmaier 1, Nikolaos Dokalis 7, Sara Gerstein 2, Sara Del Mare-Roumani 2, Sivan Amidror 2, Ori Staszewski 8, Gereon Poschmann 9, Kai Stühler 9, Frank Hirche 3, Andras Balogh 10, Stefan Kempa 11, Pascal Träger 12, Mario M Zaiss 12, Jacob Bak Holm 13, Megan G Massa 14, Henrik Bjørn Nielsen 13, Andreas Faissner 15, Carsten Lukas 16, Sören G Gatermann 17, Markus Scholz 18, Horst Przuntek 19, Marco Prinz 20, Sofia K Forslund 21, Konstanze F Winklhofer 5, Dominik N Müller 21, Ralf A Linker 6, Ralf Gold 1, Aiden Haghikia 22
Affiliations expand
PMID: 32160527
DOI: 10.1016/j.cell.2020.02.035
Abstract
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
Keywords: autoimmune diseases; immune modulation; microbiome; multiple sclerosis; neuroregeneration; propionic acid; regulatory T cells.
Copyright © 2020 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests R.G. and A.H. have filed a patent on the supportive immunomodulatory effect of C3-C8 aliphatic fatty acids.
Cited by 9 articles
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5
Clin Neurol Neurosurg
. 2019 Dec;187:105556. doi: 10.1016/j.clineuro.2019.105556. Epub 2019 Oct 12.
Relevance of calcification and contrast enhancement pattern for molecular diagnosis and survival prediction of gliomas based on the 2016 World Health Organization Classification
Yuhei Michiwaki 1, Nobuhiro Hata 2, Masahiro Mizoguchi 3, Akio Hiwatashi 4, Daisuke Kuga 5, Ryusuke Hatae 6, Yojiro Akagi 7, Takeo Amemiya 8, Yutaka Fujioka 9, Osamu Togao 10, Satoshi O Suzuki 11, Koji Yoshimoto 12, Toru Iwaki 13, Koji Iihara 14
Affiliations expand
PMID: 31639630
DOI: 10.1016/j.clineuro.2019.105556
Abstract
Objectives: The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients.
Patients and methods: We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS.
Results: A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as "molecular GBM." IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings.
Conclusion: GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting "molecular GBM" by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients.
Keywords: Calcification; Enhancement; Glioma; Molecular diagnosis; Survival; World Health Organization Classification.
Copyright © 2019 Elsevier B.V. All rights reserved.
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6
Case Reports
Front Immunol
. 2019 Aug 21;10:1964. doi: 10.3389/fimmu.2019.01964. eCollection 2019.
A Novel Splice Site Mutation in IFNGR2 in Patients With Primary Immunodeficiency Exhibiting Susceptibility to Mycobacterial Diseases
Aravind K Bandari 1 2 3, Babylakshmi Muthusamy 1 2 3, Sunil Bhat 4, Periyasamy Govindaraj 5, Pavithra Rajagopalan 1, Aparna Dalvi 6, Siddharth Shankar 3, Remya Raja 1 2 3, Kavita S Reddy 1, Manisha Madkaikar 6, Akhilesh Pandey 3 7 8
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PMID: 31497017
PMCID: PMC6712061
DOI: 10.3389/fimmu.2019.01964Free PMC article
Abstract
Primary immunodeficiency (PID) refers to a group of heterogeneous genetic disorders with a weakened immune system. Mendelian susceptibility to mycobacterial disease (MSMD) is a subset of PID in which patients exhibit defects in intrinsic and innate immunity. It is a rare congenital disorder characterized by severe and recurrent infections caused by weakly virulent mycobacteria or other environmental mycobacteria. Any delay in definitive diagnosis poses a major concern due to the confounding nature of infections and immune deficiencies. Here, we report the clinical, immunological, and genetic characteristics of two siblings (infants) with recurrent infections. There was a history of death of two other siblings in the family after BCG vaccination. Whole exome sequencing of the two affected surviving infants along with their consanguineous parents identified a novel, homozygous single nucleotide splice acceptor site variant in intron 2 of the interferon gamma receptor 2 (IFNGR2) gene. Sanger sequencing of DNA obtained from blood and fibroblasts confirmed the variant. The patients underwent bone marrow transplantation from their father as a donor. RT-PCR and Sanger sequencing of the cDNA of patients from blood samples after transplantation showed the expression of both wild type and mutant transcript expression of IFNGR2. To assess partial or complete expression of IFNGR2 mutant transcripts, fibroblasts were cultured from skin biopsies. RT-PCR and Sanger sequencing of cDNA obtained from patient fibroblasts revealed complete expression of mutant allele and acquisition of a cryptic splice acceptor site in exon 3 that resulted in deletion of 9 nucleotides in exon 3. This led to an in-frame deletion of three amino acids p.(Thr70-Ser72) located in a fibronectin type III (FN3) domain in the extracellular region of IFNGR2. This illustrates individualized medicine enabled by next generation sequencing as identification of this mutation helped in the clinical diagnosis of MSMD in the infants as well as in choosing the most appropriate therapeutic option.
Keywords: IFN gamma signaling; IFNGR2 deficiency; gene therapy; immunodeficiency; infection; non-tuberculous mycobacteria.
Cited by 1 article
36 references
3 figures
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7
Sci Rep
. 2019 Apr 29;9(1):6634. doi: 10.1038/s41598-019-43024-w.
Cortical circuit alterations precede motor impairments in Huntington's disease mice
Johanna Burgold 1, Elena Katharina Schulz-Trieglaff 1, Kerstin Voelkl 1, Sara Gutiérrez-Ángel 1, Jakob Maximilian Bader 2, Fabian Hosp 2, Matthias Mann 2, Thomas Arzberger 3 4 5, Rüdiger Klein 6 7, Sabine Liebscher 8 9 10, Irina Dudanova 11
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PMID: 31036840
PMCID: PMC6488584
DOI: 10.1038/s41598-019-43024-wFree PMC article
Abstract
Huntington's disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.
Conflict of interest statement
The authors declare no competing interests.
Cited by 6 articles
70 references
5 figures
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8
Neurosurg Rev
. 2020 Apr;43(2):749-758. doi: 10.1007/s10143-019-01117-0. Epub 2019 Jun 10.
WHO grade I meningiomas: classification-tree for prognostic factors of survival
Jean-Michel Lemée 1 2, Holger Joswig 3, Michele Da Broi 4, Marco Vincenzo Corniola 3, David Scheie 5, Karl Schaller 3 6, Eirik Helseth 4 7, Torstein R Meling 3 4 6 7
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PMID: 31183587
DOI: 10.1007/s10143-019-01117-0
Abstract
World Health Organization (WHO) grade I meningiomas are intracranial extracerebral tumors, in which microsurgery as a stand-alone therapy provides high rates of disease control and low recurrence rates. Our aim was to identify prognostic factors of overall survival and time-to-retreat (OS; TTR) in a cohort of patients with surgically managed WHO grade I meningioma. Patients with WHO grade I meningiomas from a retrospectively (1990 to 2002) and prospectively managed (2003 to 2010) databank of Oslo University Hospital, Norway, were included. The mean follow-up was 9.2 ± 5.7 years, with a total of 11,414 patient-years. One thousand three hundred fifty-five patients were included. The mean age was 58 ± 13.2, mean Karnofsky Performance Status (KPS) 92.6 ± 26.1 and female-to-male ratio 2.5:1. The 1-year, 5-year, 10-year, 15-year, and 20-year probabilities were 0.98, 0.91, 0.87, 0.84, and 0.8 for TTR. Patient age (OR 0.92 [0.91, 0.94]), male sex (OR 0.59 [0.45, 0.76]), preoperative KPS ≥ 70 (OR 2.22 [1.59, 3.13]), skull base location (OR 0.77 [0.60, 1]), and the occurrence of a postoperative hematoma (OR 0.44 [0.26, 0.76]) were identified as independent prognostic factors of OS. Patient age (OR 1.02 [1.01, 1.03]) and skull base location (OR 0.30 [0.21, 0.45]) were independent predictors of decreased PFS. Using a recursive partitioning analysis, we suggest a classification tree for the prediction of 5-year PFS based on patient and tumor characteristics. The findings from this cohort of meningioma WHO I patients helps to identify patients at risk of recurrence and tailor the therapeutic management.
Keywords: Meningioma; Overall survival; Prognostic factors; Time-to-retreat; WHO grade I.
Cited by 1 article
55 references
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9
Epilepsia
. 2020 Apr;61(4):787-797. doi: 10.1111/epi.16487. Epub 2020 Apr 3.
Adenosine kinase and adenosine receptors A 1 R and A 2A R in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP
Smriti Patodia 1 2, Beatrice Paradiso 1 2, Maria Garcia 1 2, Matthew Ellis 3, Beate Diehl 1 2, Maria Thom 1 2 3, Orrin Devinsky 4
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PMID: 32243580
DOI: 10.1111/epi.16487
Abstract
Objective: The "adenosine hypothesis of SUDEP" (sudden unexpected death in epilepsy) predicts that a seizure-induced adenosine surge combined with impaired metabolic clearance can foster lethal apnea or cardiac arrest. Changes in adenosine receptor density and adenosine kinase (ADK) occur in surgical epilepsy patients. Our aim was to correlate the distribution of ADK and adenosine A2A and A1 receptors (A2A R and A1 R) in surgical tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE/HS) with SUDEP risk factors.
Methods: In 75 cases, patients were stratified into high-risk (n = 16), medium-risk (n = 11) and low-risk (n = 48) categories according to the frequency of generalized seizures before surgery. Using whole-slide scanning Definiens image analysis we quantified the labeling index (LI) for ADK, A2A R, and A1 R in seven regions of interest: temporal cortex, temporal lobe white matter, CA1, CA4, dentate gyrus, subiculum, and amygdala and relative to glial and neuronal densities with glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN).
Results: A1 R showed predominant neuronal, A2A R astroglial, and ADK nuclear labeling in all regions but with significant variation. Compared with the low-risk group, the high-risk group had significantly lower A2A R LI in the temporal cortex. In HS cases with severe neuronal cell loss and gliosis predominantly in the CA1 and CA4 regions, significantly higher A1 R was present in the amygdala in high-risk than in low-risk cases. There was no significant difference in neuronal loss or gliosis between the risk groups or differences for ADK labeling.
Significance: Reduced cortical A2A R suggests glial dysfunction and impaired adenosine modulation in response to seizures in patients at higher risk for SUDEP. Increased neuronal A1 R in the high-risk group could contribute to periictal amygdala dysfunction in SUDEP.
Keywords: adenosine kinase; adenosine receptors; amygdala; gliosis; temporal lobe epilepsy.
© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.
50 references
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10
J Magn Reson Imaging
. 2019 Oct;50(4):1103-1113. doi: 10.1002/jmri.26681. Epub 2019 Feb 4.
23 Na MRI depicts early changes in ion homeostasis in skeletal muscle tissue of patients with duchenne muscular dystrophy
Teresa Gerhalter 1 2 3, Lena V Gast 3, Benjamin Marty 1 2, Jan Martin 3, Regina Trollmann 4, Stephanie Schüssler 4, Frank Roemer 3, Frederik B Laun 3, Michael Uder 3, Rolf Schröder 5, Pierre G Carlier 1 2, Armin M Nagel 3 6 7
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PMID: 30719784
DOI: 10.1002/jmri.26681
Abstract
Background: Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disease leading to progressive muscle wasting. Since there is a need for MRI variables that serve as early sensitive indicators of response to treatment, several quantitative MRI methods have been suggested for disease monitoring.
Purpose: To evaluate the potential of sodium (23 Na) and proton (1 H) MRI methods to assess early pathological changes in skeletal muscle of DMD.
Study type: Prospective clinical study.
Population: 23 Na and 1 H MRI of the right leg were performed in 13 patients with DMD (age 7.8 ± 2.4) and 14 healthy boys (age 9.5 ± 2.2).
Field strength/sequence: 3 T including a multiecho-spin-echo sequence, diffusion-weighted sequences, 1 H spectroscopy, 3-pt Dixon, and 23 Na ultrashort echo time sequences.
Assessment: We obtained water T2 maps, fat fraction (FF), pH, and diffusion properties of the skeletal muscle tissue. Moreover, total tissue sodium concentration (TSC) was calculated from the 23 Na sequence. Intracellular-weighted 23 Na signal (ICwS) was derived from 23 Na inversion-recovery imaging.
Statistical tests: Results from DMD patients and controls were compared using Wilcoxon rank-sum tests and repeated analysis of variance (ANOVA). Spearman-rank correlations and area under the curve (AUC) were calculated to assess the performance of the different MRI methods to distinguish dystrophic from healthy muscle tissue.
Results: FF, water T2 , and pH were higher in DMD patients (0.07 ± 0.03, 39.4 ± 0.8 msec, 7.06 ± 0.03, all P < 0.05) than in controls (0.02 ± 0.01, 36.0 ± 0.4 msec, 7.03 ± 0.02). No difference was observed in diffusion properties. TSC (26.0 ± 1.3 mM, P < 0.05) and ICwS (0.69 ± 0.05 a.u., P < 0.05) were elevated in DMD (controls: 16.5 ± 1.3 mM and 0.47 ± 0.04 a.u.). The ICwS was frequently abnormal in DMD even when water T2 , FF, and pH were in the normal range. 23 Na MRI showed higher AUC values in comparison to the 1 H methods.
Data conclusion: Sodium anomalies were regularly observed in patients with DMD compared with controls, and were present even in absence of fatty degenerative changes and water T2 increases.
Level of evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1103-1113.
Keywords: Duchenne muscular dystrophy; proton MRI; skeletal muscle; sodium MRI.
© 2019 International Society for Magnetic Resonance in Medicine.
39 references
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11
Ann Neurol
. 2020 Jul;88(1):137-147. doi: 10.1002/ana.25752. Epub 2020 May 27.
Dysregulation of the Retromer Complex System in Down Syndrome
Mary Elizabeth Curtis 1, Daohai Yu 2, Domenico Praticò 1
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PMID: 32320094
PMCID: PMC7384049
DOI: 10.1002/ana.25752Free PMC article
Abstract
Objective: Most of the patients with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by age 40. Although this increased susceptibility to AD in DS is thought to be primarily due to triplication of the amyloid precursor protein located on chromosome 21, the precise molecular mechanisms are not well understood. Recent evidence has implicated defective protein sorting and trafficking secondary to deficiencies in retromer complex proteins in AD pathogenesis. Thus, the objective of the present study is to assess the retromer complex system in DS.
Methods: Human postmortem brain tissue and fibroblasts from subjects with DS and healthy controls were examined for the various retromer protein components using Western blot analysis and reverse transcription quantitative polymerase chain reaction (RT-qPCR).
Results: Retromer recognition core proteins were significantly decreased in DS fibroblasts, and in both the hippocampi and cortices of young (age 15-40 years old) and aged (40-65 years old) subjects with DS compared with controls. Correlation analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of Aβ 1-40 and 1-42 in both hippocampus (n = 33, Spearman = -0.59 to -0.38, p ≤ 0.03 for VPS35, VPS26, VPS29, and VPS26B) and cortex tissue (n = 57, Spearman = -0.46 to -0.27, p ≤ 0.04 for VPS35, VPS26, and VPS29) of the same patients.
Interpretation: We conclude that dysregulation of the retromer complex system is an early event in the development of the AD-like pathology and cognitive decline in DS, and for this reason the system could represent a novel potential therapeutic target for DS. ANN NEUROL 2020 ANN NEUROL 2020;88:137-147.
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Conflict of interest statement
The authors have no conflicting financial interests to disclose.
28 references
6 figures
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12
Clinical Trial
Sci Rep
. 2019 Jun 19;9(1):8747. doi: 10.1038/s41598-019-45312-x.
Arterial Spin Labeling and Dynamic Susceptibility Contrast-enhanced MR Imaging for evaluation of arteriovenous shunting and tumor hypoxia in glioblastoma
S Ali Nabavizadeh 1, Hamed Akbari 2, Jeffrey B Ware 2, MacLean Nasrallah 3, Samantha Guiry 2, Stephen J Bagley 4, Arati Desai 4, Scott Levy 5, Whitney Sarchiapone 5, Timothy Prior 5, John Detre 6, Ronald L Wolf 2, Donald M O'Rourke 5, Steven Brem 5, Christos Davatzikos 2
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PMID: 31217496
PMCID: PMC6584644
DOI: 10.1038/s41598-019-45312-xFree PMC article
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. Significant challenges in the care of patients with GBM include marked vascular heterogeneity and arteriovenous (AV) shunting, which results in tumor hypoxia and inadequate delivery of systemic treatments to reach tumor cells. In this study, we investigated the utility of different MR perfusion techniques to detect and quantify arteriovenous (AV) shunting and tumor hypoxia in patients with GBM. Macrovascular shunting was present in 33% of subjects, with the degree of shunting ranging from (37-60%) using arterial spin labeling perfusion. Among the dynamic susceptibility contrast-enhanced perfusion curve features, there were a strong negative correlation between hypoxia score, DSC perfusion curve recovery slope (r = -0.72, P = 0.018) and angle (r = -0.73, P = 0.015). The results of this study support the possibility of using arterial spin labeling and pattern analysis of dynamic susceptibility contrast-enhanced MR Imaging for evaluation of arteriovenous shunting and tumor hypoxia in glioblastoma.
Conflict of interest statement
The authors declare no competing interests.
28 references
5 figures
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13
Review
Am J Surg Pathol
. 2020 Sep;44(9):1224-1234. doi: 10.1097/PAS.0000000000001512.
Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature
Jerzy Lasota 1, Małgorzata Chłopek, Bartosz Wasąg, Artur Kowalik, Jason Christiansen, Jennifer Lamoureux, Alina Kuźniacka, Anna Felisiak-Gołąbek, Yalan Liu, Tiffany Ashley R Reyes, Rishabh Saha, Abbas Agaimy, Kristyna Behenska, Wojciech Biernat, Laura Cattaneo, Giovanni Centonze, Ondrej Daum, Magdalena Daumova, Paweł Domagała, Ireneusz Dziuba, Carol E Geppert, Stanisław Góźdź, Anna Nasierowska-Guttmejer, Agnieszka Hałoń, Arndt Hartmann, Shingo Inaguma, Ewa Iżycka-Świeszewska, Maciej Kaczorowski, Małgorzata Kołos, Janusz Kopczyński, Michal Michal, Massimo Milione, Krzysztof Okoń, Rafał Pęksa, Michał Pyzlak, Janusz Ryś, Piotr Waloszczyk, Jaroslaw Wejman, Markku Miettinen
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PMID: 32804454
DOI: 10.1097/PAS.0000000000001512
Abstract
This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
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14
PLoS One
. 2020 Aug 18;15(8):e0237890. doi: 10.1371/journal.pone.0237890. eCollection 2020.
HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis
Munenori Oyama 1, Yuko Ohnuki 2, Michio Inoue 3, Akinori Uruha 4, Satoshi Yamashita 5, Sachiko Yutani 6, Jantima Tanboon 3, Jin Nakahara 1, Shingo Suzuki 7, Takashi Shiina 7, Ichizo Nishino 3, Shigeaki Suzuki 1
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PMID: 32810190
PMCID: PMC7437458
DOI: 10.1371/journal.pone.0237890Free PMC article
Abstract
Introduction: Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy, characterized by unique clinical features including finger flexor and quadriceps muscle weakness and a lack of any reliable treatment. The human leukocyte antigen (HLA)-DRB1 allele and autoantibody profiles in Japanese IBM patients have not been fully elucidated.
Methods: We studied 83 Japanese IBM patients with a mean age of 69 years (49 males and 34 females) who participated in the 'Integrated Diagnosis Project for Inflammatory Myopathies' from January 2011 to September 2016. IBM was diagnosed by histological diagnosis. Various autoantibodies were screened by RNA immunoprecipitation and enzyme-linked immunosorbent assays. HLA-DRB1 genotyping was performed using polymerase chain reaction-sequence based typing. A total of 460 unrelated healthy Japanese controls were also studied.
Results: The allele frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the IBM group than in the healthy control group (Corrected P = 0.00078, 0.00038 and 0.0046). There was a weak association between the DRB1*01:01 allele and severe leg muscle weakness and muscle atrophy. While hepatitis type C virus infection and autoantibodies to cytosolic 5'-nucleotidase 1A were found in 18 and 28 patients, respectively, no significant association with HLA-DRB1 alleles was observed.
Conclusion: Japanese IBM patients had the specific HLA-DRB1 allele and autoantibody profiles.
Conflict of interest statement
Munenori Oyama, Yuko Ohnuki, Michio Inoue, Akinori Uruha, Satoshi Yamashita, Sachiko Yutani, Jantima Tanboon, Jin Nakahara, Shingo Suzuki, Takashi Shiina, and Ichizo Nishino declare no competing interests. Shigeaki Suzuki received personal fees from Alexion Pharmaceuticals, the Japan Blood Products Organization, and Asahi Kasei Medical. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
26 references
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15
Review
Brain Tumor Pathol
. 2020 Oct;37(4):127-135. doi: 10.1007/s10014-020-00373-z. Epub 2020 Jul 5.
Primary central nervous system lymphomas associated with chronic inflammation: diagnostic pitfalls of central nervous system lymphomas
Yasuo Sugita 1, Jun Masuoka 2, Katsuharu Kameda 3, Kenji Takahashi 4, Yoshizo Kimura 5, Koichi Higaki 5, Takuya Furuta 6, Koichi Ohshima 6
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PMID: 32627089
DOI: 10.1007/s10014-020-00373-z
Abstract
In recent years, the features of lymphomas associated with chronic inflammation, referred to as diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation (DLBCL-CI), have been elucidated. DLBCL-CI is an aggressive lymphoma occurring in the context of long-standing chronic inflammation and showing an association with Epstein-Barr virus. Fibrin-associated diffuse large B-cell lymphoma (F-DLBCL) was suggested as a new and unusual form of DLBCL-CI in the most recent version of the World Health Organization classification. From the perspective of genetics, DLBCL-CI was associated with frequent TP53 mutation, MYC amplification and complex karyotypes, but cases of F-DLBCL behaved indolently and showed a relatively lower genetic complexity. In the central nervous system (CNS), several examples of DLBCL-CI and F-DLBCL have been reported. As with DLBCL-CI outside the CNS, DLBCL-CI in the CNS is an aggressive lymphoma. However, the clinical outcome of F-DLBCL in the CNS is good. Immunohistochemistry for p53 and c-Myc in DLBCL-CI and F-DLBCL in the CNS showed similar findings of those outside the CNS. However, one aggressive case showed transitional genetics and morphology between F-DLBCL and DLBCL-CI. These findings suggest that some cases of F-DLBCL in the CNS might have the potential to progress to DLBCL-CI.
Keywords: DLBCL associated with chronic inflammation; Fibrin-associated DLBCL; Primary central nervous system lymphoma.
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16
Case Reports
Eur J Med Genet
. 2020 Feb;63(2):103655. doi: 10.1016/j.ejmg.2019.04.012. Epub 2019 Apr 27.
Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type
Judith Zima 1, Alison Eaton 2, Endre Pál 3, Ágnes Till 4, Yoko A Ito 2, Jodi Warman-Chardon 5, Taila Hartley 2, Gael Cagnone 6, Bela I Melegh 4, Care4Rare Canada; Kym M Boycott 2, Béla Melegh 4, Kinga Hadzsiev 4
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PMID: 31034989
DOI: 10.1016/j.ejmg.2019.04.012
Abstract
LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement; however phenotypic variability is often observed with some individuals having earlier onset and more severe symptoms. Here, we present a family with a novel NM_005494.2:c.271T > G p.(Phe91Val) variant in DNAJB6 with a late-onset, mild and slowly progressive form of the disease, including one individual, who in her 7th decade of life has subclinical LGMD1D with only mild features on muscle biopsy and MRI. Unlike previously reported cases where missense variants affecting the Phe91 amino acid residue are associated with a more severe form of the disease, this family represents the mild end of the LGMD1D clinical spectrum. Therefore, this family adds further complexity to the genotype-phenotype correlation in DNAJB6-associated muscular dystrophies.
Keywords: DNAJB6; Exome sequencing; Genotype-phenotype correlation; LGMD1D; Limb-girdle muscular dystrophy (LGMD).
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
Cited by 2 articles
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17
J Vis Exp
. 2020 Jun 3;(160). doi: 10.3791/60296.
Abbiategrasso Brain Bank Protocol for Collecting, Processing and Characterizing Aging Brains
Tino Emanuele Poloni # 1, Valentina Medici # 2, Arenn Faye Carlos 3, Annalisa Davin 4, Arcangelo Ceretti 2, Michela Mangieri 2, Paola Cassini 5, Roberta Vaccaro 6, Daniele Zaccaria 6, Simona Abbondanza 6, Matteo Bordoni 7, Valentina Fantini 8, Elena Fogato 9, Cristina Cereda 7, Mauro Ceroni 10, Antonio Guaita 11
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PMID: 32568219
DOI: 10.3791/60296
Abstract
In a constantly aging population, the prevalence of neurodegenerative disorders is expected to rise. Understanding disease mechanisms is the key to find preventive and curative measures. The most effective way to achieve this is through direct examination of diseased and healthy brain tissue. The authors present a protocol to obtain, process, characterize and store good quality brain tissue donated by individuals registered in an antemortem brain donation program. The donation program includes a face-to-face empathic approach to people, a collection of complementary clinical, biological, social and lifestyle information and serial multi-dimensional assessments over time to track individual trajectories of normal aging and cognitive decline. Since many neurological diseases are asymmetrical, our brain bank offers a unique protocol for slicing fresh specimens. Brain sections of both hemispheres are alternately frozen (at -80 °C) or fixed in formalin; a fixed slice on one hemisphere corresponds to a frozen one on the other hemisphere. With this approach, a complete histological characterization of all frozen material can be obtained, and omics studies can be performed on histologically well-defined tissues from both hemispheres thus offering a more complete assessment of neurodegenerative disease mechanisms. Correct and definite diagnosis of these diseases can only be achieved by combining the clinical syndrome with the neuropathological evaluation, which often adds important etiological clues necessary to interpret the pathogenesis. This method can be time consuming, expensive and limited as it only covers a limited geographical area. Regardless of its limitations, the high degree of characterization it provides can be rewarding. Our ultimate goal is to establish the first Italian Brain Bank, all the while emphasizing the importance of neuropathologically verified epidemiological studies.
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18
Neurology
. 2020 Oct 19;10.1212/WNL.0000000000011031. doi: 10.1212/WNL.0000000000011031. Online ahead of print.
Derivation and utility of an Aβ-PET pathology accumulation index to estimate Aβ load
Antoine Leuzy 1, Johan Lilja 2 3 4, Christopher J Buckley 5, Rik Ossenkoppele 2 6, Sebastian Palmqvist 2 7, Mark Battle 5, Gill Farrar 5, Dietmar R Thal 8 9, Shorena Janelidze 2, Erik Stomrud 2 10, Olof Strandberg 2, Ruben Smith 2 7, Oskar Hansson 2 10
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PMID: 33077542
DOI: 10.1212/WNL.0000000000011031
Abstract
Objective: To evaluate a novel Aβ-PET based quantitative measure (Aβ accumulation index [Aβ-index]), including the assessment of its ability to discriminate between subjects based on Aβ-status using visual-read, CSF Aβ42/Aβ40 and post-mortem neuritic-plaque burden as standards of truth.
Methods: One thousand hundred twenty-one subjects (with and without cognitive impairment) scanned with Aβ-PET: Swedish BioFINDER, n = 392, [18F]flutemetamol; ADNI, n = 692, [18F]florbetapir; a phase-3 end-of-life study, n = 100, [18F]flutemetamol). The relationships between Aβ-index and standardized uptake values ratios (SUVR) from Aβ-PET were assessed. The diagnostic performance of Aβ-index and SUVR were compared when using visual reads, CSF Aβ42/Aβ40 and Aβ-histopathology as reference standards.
Results: Strong associations were observed between Aβ-index and SUVR (R2, BioFINDER, 0.951; ADNI, 0.943, end-of-life, 0.916). Both measures performed equally well in differentiating Aβ-positive from Aβ-negative subjects, with AUCs of 0.979-0.991 to detect abnormal visual reads, AUCs of 0.961-0.966 to detect abnormal CSF Aβ42/40 and AUCs of 0.820-0.823 to detect abnormal Aβ-histopathology. Both measures also showed a similar distribution across post-mortem based Aβ-phases (based on anti-Aβ 4G8 antibodies). By comparison to models using visual-read alone, the addition of the Aβ-index resulted in a significant increase in AUC and a decrease in Akaike information criterion to detect abnormal Aβ-histopathology.
Conclusion: The proposed Aβ-index showed a tight association to SUVR and carries an advantage over the latter in that it does not require the definition of regions of interest nor the use of MRI. Aβ-index may thus prove simpler to implement in clinical settings and may also facilitate the comparison of findings using different Aβ-PET tracers.
Classification of evidence: This study provides Class III evidence that the Aβ accumulation index accurately differentiates Aβ-positive from Aβ-negative subjects when compared to Aβ-PET visual reads, CSF Aβ42/Aβ40 and Aβ-histopathology.
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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19
Nat Cell Biol
. 2020 Jul;22(7):828-841. doi: 10.1038/s41556-020-0526-8. Epub 2020 Jun 15.
Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature
Bilal N Sheikh 1, Sukanya Guhathakurta 1 2, Tsz Hong Tsang 1 2, Marius Schwabenland 3, Gina Renschler 1 2, Benjamin Herquel 1, Vivek Bhardwaj 1, Herbert Holz 1, Thomas Stehle 1, Olga Bondareva 4, Nadim Aizarani 1 2, Omar Mossad 2 3, Oliver Kretz 5 6, Wilfried Reichardt 7 8 9, Aindrila Chatterjee 1, Laura J Braun 10, Julien Thevenon 11 12, Herve Sartelet 13, Thomas Blank 3, Dominic Grün 1, Dominik von Elverfeldt 7, Tobias B Huber 5, Dietmar Vestweber 10, Sergiy Avilov 1, Marco Prinz 3 14 15, Joerg M Buescher 1, Asifa Akhtar 16
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PMID: 32541879
DOI: 10.1038/s41556-020-0526-8
Abstract
Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex-Mof, Kansl2 or Kansl3-unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.
Cited by 1 article
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20
Acta Neuropathol
. 2020 Oct 19. doi: 10.1007/s00401-020-02236-5. Online ahead of print.
MOG expressing teratoma followed by MOG-IgG-positive optic neuritis
Brigitte Wildemann 1, Sven Jarius 2, Jonas Franz 3, Klemens Ruprecht 4, Markus Reindl 5, Christine Stadelmann 3
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PMID: 33078290
DOI: 10.1007/s00401-020-02236-5
No abstract available
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