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Pathological transitions in myelin membranes driven by environmental and multiple sclerosis conditions.

ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease, leading to the destruction of the myelin sheaths, the protective layers surrounding the axons. The etiology of the disease is unknown, although there are several postulated environmental factors that may contribute to it. Recently, myelin damage was correlated to structural phase transition from a healthy stack of lamellas to a diseased inverted hexagonal phase as a result of the altered lipid stoichiometry and low myelin basic protein (MBP) content. In this work, we show that environmental conditions, such as buffer salinity and temperature, induce the same pathological phase transition as in the case of the lipid composition in the absence of MBP. These phase transitions have different transition points, which depend on the lipid's compositions, and are ion specific. In extreme environmental conditions, we find an additional dense lamellar phase and that the native lipid composition results in similar pathology as the diseased composition. These findings demonstrate that several local environmental changes can trigger pathological structural changes. We postulate that these structural modifications result in myelin membrane vulnerability to the immune system attacks and thus can help explain MS etiology.

SUBMITTER: Shaharabani R

PROVIDER: S-EPMC6217380 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Pathological transitions in myelin membranes driven by environmental and multiple sclerosis conditions.

Shaharabani Rona R Ram-On Maor M Talmon Yeshayahu Y Beck Roy R

Proceedings of the National Academy of Sciences of the United States of America 20181015 44

Multiple sclerosis (MS) is an autoimmune disease, leading to the destruction of the myelin sheaths, the protective layers surrounding the axons. The etiology of the disease is unknown, although there are several postulated environmental factors that may contribute to it. Recently, myelin damage was correlated to structural phase transition from a healthy stack of lamellas to a diseased inverted hexagonal phase as a result of the altered lipid stoichiometry and low myelin basic protein (MBP) cont ...[more]

PMID: 30322944

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Project description:Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.

Project description:ObjectivesEvolution of multiple chronic conditions (MCC) follows a complex stochastic process, influenced by several factors including the inter-relationship of existing conditions, and patient-level risk factors. Nearly 20% of citizens aged 18 years and older are burdened with two or more (multiple) chronic conditions (MCC). Treatment for people living with MCC currently accounts for an estimated 66% of the Nation's healthcare costs. However, it is still not known precisely how MCC emerge and accumulate among individuals or in the general population. This study investigates major patterns of MCC transitions in a diverse population of patients and identifies the risk factors affecting the transition process.MethodsA Latent regression Markov clustering (LRMCL) algorithm is proposed to identify major transitions of four MCC that include hypertension (HTN), depression, Post- Traumatic Stress Disorder (PTSD), and back pain. A cohort of 601,805 individuals randomly selected from the population of Iraq and Afghanistan war Veterans (IAVs) who received VA care during three or more years between 2002-2015, is used for training the proposed LRMCL algorithm.ResultsTwo major clusters of MCC transition patterns with 78% and 22% probability of membership respectively were identified. The primary cluster demonstrated the possibility of improvement when the number of MCC is small and an increase in probability of MCC accumulation as the number of co- morbidities increased. The second cluster showed stability (no change) of MCC overtime as the major pattern. Age was the most significant risk factor associated with the most probable cluster for each IAV.ConclusionsThese findings suggest that our proposed LRMCL algorithm can be used to describe and understand MCC transitions, which may ultimately allow healthcare systems to support optimal clinical decision- making. This method will be used to describe a broader range of MCC transitions in this and non-VA populations, and will add treatment information to see if models including treatments and MCC emergence can be used to support clinical decision-making in patient care.

Dataset Information

Pathological transitions in myelin membranes driven by environmental and multiple sclerosis conditions.

Publications

Pathological transitions in myelin membranes driven by environmental and multiple sclerosis conditions.

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