Reduced Creatine Kinase B Activity in Multiple Sclerosis Normal Appearing White Matter

Steen, Christel; Wilczak, Nadine; Hoogduin, Johannes M.; Koch, Marcus; Keyser, Jacques De

doi:10.1371/journal.pone.0010811

Cited by 45 publications

(49 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Husted et al (1994) found significantly increased PCr/total 31 P ratio values in the normal appearing white matter of the centrum semiovale, but not in focal MS lesions of MS patients versus healthy controls. Steen et al (2010) corroborated these findings by detecting significantly increased PCr/b-ATP and PCr/total 31 P ratios in the normal appearing white matter of the centrum semiovale of MS patients, compared with healthy controls.…”

Section: Phosphocreatine Metabolismsupporting

confidence: 63%

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

Cambron

D’haeseleer

Lochard

et al. 2012

J Cereb Blood Flow Metab

Self Cite

104

View full text Add to dashboard Cite

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in b 2 adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

show abstract

Section: Phosphocreatine Metabolismsupporting

confidence: 63%

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

Cambron

D’haeseleer

Lochard

et al. 2012

J Cereb Blood Flow Metab

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…Chronic lesions and the remaining NAWM and NAGM appeared hypoperfused due to a reduced axonal activity [167], with a lower K + release in the periaxonal and perivascular space, reduced astrocyte metabolism [168] and reduced arteriolar vasodilatation [169] (Figure 2C). In this context it is not surprising to find elevated VEGF signalling [58], increased vessel density and angiogenic endothelial cells in MS chronic demyelinated lesions and NAWM [22] as a frustrated attempt to overcome the chronic hypoperfusion.…”

Section: Chronic Hypoperfusion Hypoxia and Angiogenesismentioning

confidence: 99%

“…These molecules could be responsible for mitochondrial dysfunction [173], distal oligodendropathy [177], apoptotic-like cell death and axonal injury [178]. In MS patients, these pathologic mechanisms are associated with astrocyte dysfunction [167][168][169], which could explain the arteriolar vasoconstriction in the presence of high metabolic demands (neurovascular uncoupling), accounting for so severe a hypoperfusion state as to result in hypoxia, and ultimately responsible for disease progression. In fact, the level of VEGF expression in resident astrocytes and neurons appears increased in progressive MS patients [35,58], as well as in RR-MS [35], and a reduced level of VEGF has been detected only in non-resident mononuclear cells in CSF and peripheral blood [53,63].…”

Section: Chronic Hypoperfusion Hypoxia and Angiogenesismentioning

confidence: 99%

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Girolamo

Coppola

Ribatti

et al. 2014

Acta Neuropathologica Communications

View full text Add to dashboard Cite

Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood-brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

show abstract

“…Previous works showed increased PCr in the normal appearing white matter (NAWM) of MS patients compared to healthy controls [10,11,12,13]. Although NAWM ATP might be used as a biomarker of disease severity, the relationship between ATP metabolites and Expanded Disability Status Scale (EDSS) remains unclear in RRMS and SPMS.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

et al. 2017

View full text Add to dashboard Cite

Background/Aims: Phosphorus magnetic resonance spectroscopy (³¹P-MRS) has previously shown abnormal changes in energy metabolites in the brain of multiple sclerosis (MS) patients. However, the relationship between these energy metabolites - particularly adenosine triphosphate (ATP) - and the disease severity remains unclear. The objective of this study was to determine whether measuring ATP metabolites can help to predict disease severity in MS patients. Methods:³¹P-MRS at 3 tesla was performed in 9 relapsing remitting (RRMS), 9 secondary progressive MS patients (SPMS), and 10 age-matched healthy controls. ATP metabolites (expressed as %) in normally appearing white matter of the centrum semiovale were compared between patients and healthy controls. The relationship between Expanded Disability Status Scale (EDSS) and ATP metabolites was evaluated. Results: RRMS and SPMS patients had higher phosphocreatine (PCr) and lower phosphodiesters than healthy controls. In addition, RRMS patients had higher β-ATP% than SPMS patients. β-ATP% was negatively correlated with EDSS in all patients. Conclusion: Our findings suggest a defective PCr metabolism in both patient groups, and a higher state of energy production in RRMS that might reflect a compensatory mechanism in face of the increased needs. The correlation of β-ATP with EDSS makes it a candidate biomarker for assessing MS disease severity.

show abstract

Reduced Creatine Kinase B Activity in Multiple Sclerosis Normal Appearing White Matter

Cited by 45 publications

References 40 publications

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity

Contact Info

Product

Resources

About