Chronic Demyelination and Axonal Degeneration in Multiple Sclerosis: Pathogenesis and Therapeutic Implications.

PURPOSE OF REVIEW: Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). Inflammatory attacks in MS lead to both demyelination and axonal damage. However, due to incomplete remyelination most MS lesions remain chronically demyelinated. In parallel, there is axonal degeneration in the CNS of MS patients, contributing to progressive disability. There are currently no approved therapies that adequately restore myelin or protect axons from degeneration. In this review, we will discuss the pathophysiology of axonal loss and chronic demyelination in MS and how understanding this pathophysiology is leading to the development of new MS therapeutics. RECENT FINDINGS: Ongoing research into the function of oligodendrocytes and myelin has revealed the importance of their relationship with neuronal health. Demyelination in MS leads to a number of pathophysiologic changes contributing to axonal generation. Among these are mitochondrial dysfunction, persistent neuroinflammation, and the effects of reactive oxygen and nitrogen species. With this information, we review currently approved and investigational therapies designed to restore lost or damaged myelin and protect against neuronal degeneration. The development of therapies to restore lost myelin and protect neurons is a promising avenue of investigation for the benefit of patients with MS.

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).

Autoimmune diseases of the brain, imaging and clinical review.

There is an extensive spectrum of autoimmune entities that can involve the central nervous system, which has expanded with the emergence of new imaging modalities and several clinicopathologic entities. Clinical presentation is usually non-specific, and imaging has a critical role in the workup of these diseases. Immune-mediated diseases of the brain are not common in daily practice for radiologists and, except for a few of them such as multiple sclerosis, there is a vague understanding about differentiating them from each other based on the radiological findings. In this review, we aim to provide a practical diagnostic approach based on the unique radiological findings for each disease. We hope our diagnostic approach will help radiologists expand their basic understanding of the discussed disease entities and narrow the differential diagnosis in specific clinical scenarios. An understanding of unique imaging features of these disorders, along with laboratory evaluation, may enable clinicians to decrease the need for tissue biopsy.

Autoimmune disease of head and neck, imaging, and clinical review.

Autoimmune disease of the head and neck (H&N) could be primary or secondary to systemic diseases, medications, or malignancies. Immune-mediated diseases of the H&N are not common in daily practice of radiologists; the diagnosis is frequently delayed because of the non-specific initial presentation and lack of familiarity with some of the specific imaging and clinical features. In this review, we aim to provide a practical diagnostic approach based on the specific radiological findings for each disease. We hope that our review will help radiologists expand their understanding of the spectrum of the discussed disease entities, help them narrow the differential diagnosis, and avoid unnecessary tissue biopsy when appropriate based on the specific clinical scenarios.

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons.

The myelination of axons by oligodendrocytes is a highly complex cell-to-cell interaction. Oligodendrocytes and axons have a reciprocal signaling relationship in which oligodendrocytes receive cues from axons that direct their myelination, and oligodendrocytes subsequently shape axonal structure and conduction. Oligodendrocytes are necessary for the maturation of excitatory domains on the axon including nodes of Ranvier, help buffer potassium, and support neuronal energy metabolism. Disruption of the oligodendrocyte-axon unit in traumatic injuries, Alzheimer's disease and demyelinating diseases such as multiple sclerosis results in axonal dysfunction and can culminate in neurodegeneration. In this review, we discuss the mechanisms by which demyelination and loss of oligodendrocytes compromise axons. We highlight the intra-axonal cascades initiated by demyelination that can result in irreversible axonal damage. Both the restoration of oligodendrocyte myelination or neuroprotective therapies targeting these intra-axonal cascades are likely to have therapeutic potential in disorders in which oligodendrocyte support of axons is disrupted.

A clinical decision rule predicting outcomes of emergency department patients with altered mental status.

STUDY OBJECTIVE: Approximately 5% of emergency department patients present with altered mental status (AMS). AMS is diagnostically challenging because of the wide range of causes and is associated with high mortality. We sought to develop a clinical decision rule predicting admission risk among emergency department (ED) patients with AMS. METHODS: Using retrospective chart review of ED encounters for AMS over a 2-month period, we recorded causes of AMS and numerous clinical variables. Encounters were split into those admitted to the hospital ("cases") and those discharged from the ED ("controls"). Using the first month's data, variables correlated with hospital admission were identified and narrowed using univariate and multivariate statistics, including recursive partitioning. These variables were then organized into a clinical decision rule and validated on the second month's data. The decision rule results were also compared to 1-year mortality. RESULTS: We identified 351 encounters for AMS over a 2-month period. Significant contributors to AMS included intoxication and chronic disorder decompensation. ED data predicting hospital admission included vital sign abnormalities, select lab studies, and psychiatric/intoxicant history. The decision rule sorted patients into low, moderate, or high risk of admission (11.1%, 44.3%, and 89.1% admitted, respectively) and was predictive of 1-year mortality (low-risk group 1.8%, high-risk group 34.3%). CONCLUSIONS: We catalogued common causes for AMS among patients presenting to the ED, and our data-driven decision tool triaged these patients for risk of admission with good predictive accuracy. These methods for creating clinical decision rules might be further studied and improved to optimize ED patient care.

Reduced Noradrenergic Signaling in the Spleen Capsule in the Absence of CB1 and CB2 Cannabinoid Receptors.

The spleen is a visceral organ that contracts during hypoxia to expel erythrocytes and immune cells into the circulation. Spleen contraction is under the control of noradrenergic sympathetic innervation. The activity of noradrenergic neurons terminating in the spleen capsule is regulated by α2-adrenergic receptors (AR). Interactions between endogenous cannabinoid signaling and noradrenergic signaling in other organ systems suggest endocannabinoids might also regulate spleen contraction. Spleens from mice congenitally lacking both CB1 and CB2 cannabinoid receptors (Cnr1 -/- /Cnr2 -/- mice) were used to explore the role of endocannabinoids in spleen contraction. Spleen contraction in response to exogenous norepinephrine (NE) was found to be significantly lower in Cnr1 -/- /Cnr2 -/- mouse spleens, likely due to decreased expression of capsular α1AR. The majority of splenic Cnr1 mRNA expression is by cells of the spleen capsule, suggestive of post-synaptic CB1 receptor signaling. Thus, these studies demonstrate a role for CB1 and/or CB2 in noradrenergic splenic contraction.

Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice.

Motor dysfunctions of Parkinson Disease (PD) are due to the progressive loss of midbrain nigrostriatal dopamine (NSDA) neurons. Evidence suggests a role for cannabinoid receptors in the neurodegeneration of these neurons following neurotoxicant-induced injury. This work evaluates NSDA neurons in CB1/CB2 knockout (KO) mice and tests the hypothesis that CB1/CB2 KO mice are more susceptible to neurotoxicant exposure. NSDA neuronal indices were assessed using unbiased stereological cell counting, high pressure liquid chromatography coupled with electrochemical detection or mass spectrometry, and Western blot. Results reveal that CB1 and CB2 cannabinoid receptor signaling is not necessary for the maintenance of a normally functioning NSDA neuronal system. Mice lacking CB1 and CB2 receptors were found to be equally susceptible to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). These studies support the use of CB1/CB2 KO mice for investigating the cannabinoid receptor-mediated regulation of the NSDA neuronal system in models of PD.