comprehensive-autopsy-program-for-individuals-with-multiple-sclerosis

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis

We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 ...

Cleveland Clinic

Clinical investigation of autologous hematopoietic stem cell transplantation (HSCT) as therapy for multiple sclerosis (MS) has been ongoing for over a decade. While several phase II studies have been finalized or are in progress, no definitive prospective randomized studies comparing HSCT versus alternative therapies for MS have been completed. In this conference report of North American and European experts who are involved in the care of MS patients, including neurologists and HSCT physicians, and representatives of the Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplantation (EBMT), we (1) critically review progress to date in HSCT for MS; (2) describe current registry based projects including long-term follow-up studies in HSCT for MS and harmonization of the MS disease-specific research forms that will be used in future by both databases; (3) discuss challenges in study design for a prospective randomized clinical trial of HSCT versus alternative therapy for MS such as feasibility, and the importance of multidisciplinary clinical teams, need for a large sample size and duration of observation required for outcomes assessment; and (4) address future directions in HSCT therapy for MS. To undertake a definitive multicenter clinical trial in autologous HSCT for MS, it will be important to begin well in advance to assemble the team, evaluate proposals for study design, and consider options for the infrastructure and logistical support that will be needed. International collaboration, including partnership with the CIBMTR and EBMT, may be desirable and may in fact be critical for successful completion of a definitive comparative study.

Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies.

MRI has rapidly become a leading research tool in the study of multiple sclerosis (MS). Conventional imaging is useful in diagnosis and management of the inflammatory stages of MS but has limitations in describing the degree of tissue injury and cause of progressive disability seen in later stages. Advanced MRI techniques hold promise for filling this void. These imaging tools hold great promise to increase understanding of MS pathogenesis and provide greater insight into the efficacy of new MS therapies.

Advanced MRI in multiple sclerosis: current status and future challenges.

Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.

Clinically feasible MTR is sensitive to cortical demyelination in MS.

Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain.

Cognitive decline is a common symptom in multiple sclerosis patients, with profound effects on the quality of life. A nonhuman primate model of multiple sclerosis would be best suited to test the effects of demyelination on complex cognitive functions such as learning and reasoning. Cuprizone has been shown to reliably induce brain demyelination in mice. To establish a nonhuman primate model of multiple sclerosis, young adult cynomolgus monkeys were administered cuprizone per os as a dietary supplement. The subjects received increasing cuprizone doses (0.3-3% of diet) for up to 18 weeks. Magnetic resonance imaging and immunohistological analyses did not reveal demyelination in these monkeys. 

Cuprizone does not induce CNS demyelination in nonhuman primates.

A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.

Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis.

Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration.

Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis.

Detecting cortical demyelination in patients with multiple sclerosis (MS) is difficult. Using magnetic resonance imaging (MRI), ratio maps of T1-weighted (T1w) and T2-weighted (T2w) images may be sensitive to cortical myelin levels. In this MRI-histological study, postmortem in situ scans were acquired from 6 cadavers with MS on a 3T MRI machine. Immunocytochemistry was used to correlate myelin status and cortical T1w/T2w measures. The results showed that the T1w/T2w values significantly differed between demyelinated and myelinated cortex (p < 0.001). The T1w/T2w ratio maps may be a relatively simple, clinically feasible method to assess cortical demyelination. Ann Neurol 2017;82:635-639.

T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis.

Purpose To determine if magnetic resonance (MR) imaging metrics can estimate primary motor cortex (PMC) motor neuron (MN) density in patients with amyotrophic lateral sclerosis (ALS). Materials and Methods Between 2012 and 2014, in situ brain MR imaging was performed in 11 patients with ALS (age range, 35-81 years; seven women and four men) soon after death (mean, 5.5 hours after death; range, 3.2-9.6 hours). The brain was removed, right PMC (RPMC) was excised, and MN density was quantified. RPMC metrics (thickness, volume, and magnetization transfer ratio) were calculated from MR images. Regression modeling was used to estimate MN density by using RPMC and global MR imaging metrics (brain and tissue volumes); clinical variables were subsequently evaluated as additional estimators. Models were tested at in vivo MR imaging by using the same imaging protocol (six patients with ALS; age range, 54-66 years; three women and three men). Results RPMC mean MN density varied over a greater than threefold range across patients and was estimated by a linear function of normalized gray matter volume (adjusted R = 0.51; P = .008; <10% error in most patients). When considering only sporadic ALS, a linear function of normalized RPMC and white matter volumes estimated MN density (adjusted R = 0.98; P = .01; <10% error in all patients). In vivo data analyses detected decreases in MN density over time. Conclusion PMC mean MN density varies widely in end-stage ALS possibly because of disease heterogeneity. MN density can potentially be estimated by MR imaging metrics.  RSNA, 2018 Online supplemental material is available for this article.

MR Imaging-based Estimation of Upper Motor Neuron Density in Patients with Amyotrophic Lateral Sclerosis: A Feasibility Study.

Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination.

Article	Year
Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation\| PubMed ID: 20304084	2010
Advanced MRI in multiple sclerosis: current status and future challenges. Neurologic clinics\| PubMed ID: 21439446	2011
Clinically feasible MTR is sensitive to cortical demyelination in MS. Neurology\| PubMed ID: 23269598	2013
Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain. Nature communications\| PubMed ID: 25047355	2014
Cuprizone does not induce CNS demyelination in nonhuman primates. Annals of clinical and translational neurology\| PubMed ID: 25750925	2015
Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England)\| PubMed ID: 27246142	2017
Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet (London, England)\| PubMed ID: 27291994	2016
Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England)\| PubMed ID: 28617152	2018
T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Annals of neurology\| PubMed ID: 28833377	2017
MR Imaging-based Estimation of Upper Motor Neuron Density in Patients with Amyotrophic Lateral Sclerosis: A Feasibility Study. Radiology\| PubMed ID: 29361242	2018
Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. The Lancet. Neurology\| PubMed ID: 30143361	2018

Jacqueline Chen

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