Showing papers by "Samuel K. Ludwin published in 2017"

An updated histological classification system for multiple sclerosis lesions

Abstract: Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. Inactive lesions are almost completely lacking macrophages/microglia. Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. For this classification of MS lesions, identification of myelin with histological stains [such as luxol fast blue-PAS] or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination.

Sublethal oligodendrocyte injury: A reversible condition in multiple sclerosis?

Abstract: Objective: Degeneration of oligodendroglial distal processes has been identified as an early event in MS lesion development. Our objective was to further define the development of the “dying-back” oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain-derived oligodendrocytes. Methods In situ analyses were performed on glutaraldehyde-fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain-derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose). Results: In situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established. In vitro studies indicated that oligodendrocyte process retraction that was linked to reduced glycolytic respiratory activity is reversible until a critical time point. Subsequent cell death was not linked to caspase-3 dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity. Interpretation: Our findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies on the mechanisms underlying subsequent adult human oligodendrocyte cell death. This article is protected by copyright. All rights reserved.

Dilemmas in medical ethics in the age of big data

Abstract: The new genome mapping techniques and the Watson artificial intelligence technology are excellent examples, facilitating the scanning of thousands of scientific data, articles, and other reports and producing in mere hours or days computer-generated answers to questions that otherwise would take months or years. This holds true for advances in science in general and for our purposes, medical practice, and research in particular. There are also profound implications for government policy and funding, and insurance costs. However, these advances inevitably raise concerns over the potential for harm. Societies have frequently dealt post facto with practical, legal, and ethical questions posed by undesirable side effects or outcomes, both anticipated and unanticipated. Many legal and ethical advances have followed rather than preceded these technological changes, and as we struggle to address these issues, the rapid discoveries are already bringing further unforeseen challenges. The original Baltimore/Asilomar rules on genetic manipulation were prompted by molecular genetic discoveries and have been more recently reinforced to meet the challenges posed by the new CRISPR technology. At an earlier time, it was the ethical lapses of the Tuskegee study, which prompted the promulgation of the Common Rule for ethical oversight in the United States.1,2