Iron heterogeneity in MS: Patterns can be separated (UPDATED)

A forum to discuss research on the origins of MS and its development.
Post Reply
User avatar
frodo
Family Elder
Posts: 1749
Joined: Wed Dec 02, 2009 3:00 pm
Contact:

Iron heterogeneity in MS: Patterns can be separated (UPDATED)

Post by frodo »

Iron heterogeneity in early active multiple sclerosis lesions.

https://europepmc.org/article/med/33244761

Abstract

OBJECTIVE:

Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.

METHODS:

We used synchrotron X-ray fluorescence imaging, histology and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.

RESULTS:

Immunopattern II early active lesions contain 64% more iron (95%CI: 17%, 127%; p=0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95%CI: 3%, 64%; p=0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95%CI: -40%, -14%; p<0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p<0.001). Micro-focused X-ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, while macrophages in immunopattern III lesions contain little iron.

INTERPRETATION:

Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions.

This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin or different demyelination mechanisms, and paves the way for developing new or using existing iron-sensitive MRI techniques to differentiate among immunopatterns in the general non-biopsied MS patient population.
Last edited by frodo on Fri Sep 24, 2021 12:46 am, edited 1 time in total.
User avatar
frodo
Family Elder
Posts: 1749
Joined: Wed Dec 02, 2009 3:00 pm
Contact:

Updates

Post by frodo »

Update 1

Magnetic Resonance Imaging Correlates of Multiple Sclerosis Immunopathological Patterns

https://onlinelibrary.wiley.com/doi/ful ... /ana.26163

Abstract

Objective

Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I–III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers.

Methods

We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112).

Results

A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients.

Interpretation

We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination.

- - - - -

Update 2

Common metabolics of the four patterns:

https://link.springer.com/article/10.11 ... 21-02305-w

Altered substrate metabolism in neurodegenerative disease: new insights from metabolic imaging

MS is a chronic inflammatory and neurodegenerative disease in which immune cells cause demyelination and neuronal damage leading to cognitive decline. The disease has multiple clinical, radiologic, and histologic presentations. It is currently not known whether the inflammatory or neurodegenerative process is primary or secondary, and it is likely that pathogenesis is variable among patients, thus giving rise to different presentations [46, 115,116,117,118]. Although the disease progression is variable, most patients experience relapsing remitting multiple sclerosis (RRMS) characterized by periods of muscle weakness, blindness, double vision, trouble with sensation, and trouble with coordination, followed by total or partial recovery. In roughly 50% of patients, RRMS proceeds to secondary progressive multiple sclerosis (SPMS) where patients experience progressive deterioration. SPMS is typically diagnosed based on a history of progressive worsening of symptoms following a relapsing course of the disease. In some patients, the disease causes progressive damage from the onset with no periods of relapse. This form is termed primary progressive multiple sclerosis (PPMS). The speed of deterioration occurs at a similar rate in PPMS as it does in SPMS [119].

Four types of lesions have been characterized in MS. 20% of MS patients have immunopattern I lesions have T-cell inflammation, activated microglia, myelin-laden macrophages, and active demyelination suggesting that activated macrophages release toxic products that drive the demyelination process [120]. Approximately 50% of patients have immunopattern II lesions. These lesions are characterized by T-lymphocyte and macrophage infiltration, immunoglobulin deposition and complement activation on myelin. Immunopattern III lesions are characterized by oligodendrocyte apoptosis, microglial activation, T-cell inflammation and loss of myelin-associated glycoprotein, 2,3-cyclic nucleotide-3-phosphodiestarase [120]. This form describes about 29% of MS patients. The final form, immunopattern IV lesions are defined by non-apoptotic oligodendrocyte death and comprise only 1% of MS patients.

Regardless of the form, metabolic disturbances are central to the pathogenesis of MS. For example there is a growing body of evidence to suggest that mitochondrial dysfunction may underlie the neurodegeneration in MS, and is often present at the onset of clinical symptoms [121]. Dysfunctional mitochondria over-produce ROS, which can cause damage to proteins, lipids, DNA, and mitochondrial DNA (mtDNA) leading to cell damage and death [122,123,124]. OLs are particularly susceptible to damage by ROS due to their high metabolic rate and reliance on mitochondrial respiration to fuel the production of myelin proteins. Neurons are also susceptible to damage by ROS as they rely heavily on the TCA cycle to generate ATP. Astrocytes on the other hand are more glycolysis-dependent and therefore less affected by mitochondrial dysfunction and damage. Microglia become activated in response to the release of inflammatory mediators that are released by other microglia or infiltrating macrophages leading to further ROS generation and damage to nearby cells [125]. Microglia switch increased glucose utilization and increased fatty acid synthesis due to activation of mTOR and disruption of the TCA cycle [125]. Intracellular metabolites like malonyl-CoA in activated microglia also prevent fatty acids from associating with carnitine acyltransferase, preventing their entry into mitochondria, and thus inhibiting FAO [125].

Like AD and PD, metabolic alterations appear to be a critical component, if not causative, to the development and progression of MS. Importantly, AD, PD and MS are all characterized by the lack of a true disease-modifying therapy that is able to reverse or halt disease progression. This can be due to many factors like drug half-life, penetration of the active form of a drug into the BBB, the timing of the intervention, or ability of the drug to reach its target, inadequate bioavailability of the drug, or patient intolerance of therapy to name a few. Regardless of the reason for the lack of disease-modifying therapy, it is plausible to suggest that therapeutics aimed at restoring mitochondrial function may be an improved strategy that may rescue an increased susceptibility to develop ND in some individuals [126, 127]. To validate this hypothesis, further research is needed to define the time, region, and cell-specific changes in oxidative metabolism. Although current imaging modalities can measure changes in brain metabolism, the resolution is often lacking to determine cell-specific metabolic alterations. Going forward we will review the current range of methods used to visualize brain metabolism and propose FLIM as an emerging modality with sufficient resolution to empirically determine metabolic changes leading to ND.
Post Reply
  • Similar Topics
    Replies
    Views
    Last post

Return to “MS Etiology and Pathogenesis”