Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis

Cader, Sarah; Johansen‐Berg, Heidi; Wylezińska, M; Palace, Jackie; Behrens, Timothy E.J.; Smith, Stephen M.; Matthews, Paul M.

doi:10.1016/j.neuroimage.2007.02.036

Cited by 95 publications

(83 citation statements)

References 58 publications

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“…This suggests that FA in the CC reflects primarily fiber density rather than the degree of myelination or axon diameter. Furthermore, patients with multiple sclerosis showed a direct correlation between FA and CC cross-sectional area (Cader et al, 2007). Because, in a postmortem analysis, patients with multiple sclerosis also exhibited a direct correlation between axon density and CC cross-sectional area (Evangelou et al, 2000), this supports further the notion that FA in the CC is significantly influenced by axon density.…”

Section: Correlation Between Fractional Anisotropy and Interhemisphersupporting

confidence: 67%

Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function

Wahl¹,

Lauterbach-Soon²,

Hattingen³

et al. 2007

J. Neurosci.

384

330

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The corpus callosum (CC) is the principal white matter fiber bundle connecting neocortical areas of the two hemispheres. Although an object of extensive research, important details about the anatomical and functional organization of the human CC are still largely unknown. Here we focused on the callosal motor fibers (CMFs) that connect the primary motor cortices (M1) of the two hemispheres. Topography and somatotopy of CMFs were explored by using a combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure. CMF microstructure was assessed by fractional anisotropy (FA), and CMF functional connectivity between the hand areas of M1 was measured by interhemispheric inhibition using paired-pulse transcranial magnetic stimulation. CMFs mapped onto the posterior body and isthmus of the CC, with hand CMFs running significantly more anteriorly and ventrally than foot CMFs. FA of the hand CMFs but not FA of the foot CMFs correlated linearly with interhemispheric inhibition between the M1 hand areas. Findings demonstrate that CMFs connecting defined body representations of M1 map onto a circumscribed region in the CC in a somatotopically organized manner. The significant and topographically specific positive correlation between FA and interhemispheric inhibition strongly suggests that microstructure can be directly linked to functional connectivity. This provides a novel way of exploring human brain function that may allow prediction of functional connectivity from variability of microstructure in healthy individuals, and potentially, abnormality of functional connectivity in neurological or psychiatric patients.

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Section: Correlation Between Fractional Anisotropy and Interhemisphersupporting

confidence: 67%

Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function

Wahl¹,

Lauterbach-Soon²,

Hattingen³

et al. 2007

J. Neurosci.

384

330

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“…Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS, which results in progressive neurological disability (Bjartmar et al, 2000;Noseworthy et al, 2000). Cortical gray matter pathology, including demyelination, axonal degeneration, and brain atrophy, is recognized as a major factor contributing to disability in MS (Inglese et al, 2004;Bö et al, 2006;Fisher et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Cortical gray matter pathology, including demyelination, axonal degeneration, and brain atrophy, is recognized as a major factor contributing to disability in MS (Inglese et al, 2004;Bö et al, 2006;Fisher et al, 2008). Previous studies suggest that mitochondrial defects, including reductions in neuronal expression of nuclear encoded mitochondrial electron transport chain genes, decreased synthesis of the neuronal mitochondrial metabolite N-acetylaspartate (NAA), and inhibition of mitochondrial respiration contribute to cortical pathology in MS (Dutta et al, 2006;Pandit et al, 2009;Broadwater et al, 2011;Campbell et al, 2011;Li et al, 2013;Witte et al, 2013); however, the mechanisms involved in these mitochondrial changes are not clear.…”

Section: Introductionmentioning

confidence: 99%

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis

Singhal¹,

Arning

et al. 2015

J. Neurosci.

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Mitochondrial changes, including decreased expression of electron transport chain subunit genes and impaired energetic, have been reported in multiple sclerosis (MS), but the mechanisms involved in these changes are not clear. To determine whether epigenetic mechanisms are involved, we measured the concentrations of methionine metabolites by liquid chromatography tandem mass spectrometry, histone H3 methylation patterns, and markers of mitochondrial respiration in gray matter from postmortem MS and control cortical samples. We found decreases in respiratory markers as well as decreased concentrations of the methionine metabolites S-adenosylmethionine, betaine, and cystathionine in MS gray matter. We also found expression of the enzyme betaine homocysteine methyltransferase in cortical neurons. This enzyme catalyzes the remethylation of homocysteine to methionine, with betaine as the methyl donor, and has previously been thought to be restricted to liver and kidney in the adult human. Decreases in the concentration of the methyl donor betaine were correlated with decreases in histone H3 trimethylation (H3K4me3) in NeuNϩ neuronal nuclei in MS cortex compared with controls. Mechanistic studies demonstrated that H3K4me3 levels and mitochondrial respiration were reduced in SH-SY5Y cells after exposure to the nitric oxide donor sodium nitroprusside, and betaine was able to rescue H3K4me3 levels and respiratory capacity in these cells. Chromatin immunoprecipitation experiments showed that betaine regulates metabolic genes in human SH-SY5Y neuroblastoma cells. These data suggest that changes to methionine metabolism may be mechanistically linked to changes in neuronal energetics in MS cortex.

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“…In fact measurements obtained from the corpus callosum of patients with CDMS, via the sensitive diffusion fractional anisotropy, could demonstrate reduced size which correlated with patient EDSS but no such correlation could be seen with reduced NAA levels relative to tissue water [40]. Furthermore, while the MRS analysis from the spinal cords of patients primarily with SPMS clearly demonstrated reduced NAA levels with excellent correlation to only moderate EDSS and tissue atrophy [41].…”

Section: Current Imaging Techniquesmentioning

confidence: 94%

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

Lee

Taghian

Petratos

2014

Acta Neuropathol Commun

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Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na + and Ca 2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.

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Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis

Cited by 95 publications

References 58 publications

Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function

Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

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