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Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis.

ABSTRACT: Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2(+) cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2(+) cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.

SUBMITTER: Kang SH

PROVIDER: S-EPMC3637847 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis.

Kang Shin H SH Li Ying Y Fukaya Masahiro M Lorenzini Ileana I Cleveland Don W DW Ostrow Lyle W LW Rothstein Jeffrey D JD Bergles Dwight E DE

Nature neuroscience 20130331 5

Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2(+) cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal co ...[more]

PMID: 23542689

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Project description:Therapeutic management and research in Amyotrophic Laterals Sclerosis (ALS) have been limited by the substantial heterogeneity in progression and anatomical spread that are endemic of the disease. Neuroimaging biomarkers represent powerful additions to the current monitoring repertoire but have yielded inconsistent associations with clinical scores like the ALS functional rating scale. The D50 disease progression model was developed to address limitations with clinical indices and the difficulty obtaining longitudinal data in ALS. It yields overall disease aggressiveness as time taken to reach halved functionality (D50); individual disease covered in distinct phases; and calculated functional state and calculated functional loss as acute descriptors of local disease activity. It greatly reduces the noise of the ALS functional rating scale and allows the comparison of highly heterogeneous disease and progression subtypes. In this study, we performed Voxel-Based Morphometry for 85 patients with ALS (60.1 ± 11.5 years, 36 female) and 62 healthy controls. Group-wise comparisons were performed separately for gray matter and white matter using ANCOVA testing with threshold-free cluster enhancement. ALS-related widespread gray and white matter density decreases were observed in the bilateral frontal and temporal lobes (p < 0.001, family-wise error corrected). We observed a progressive spread of structural alterations along the D50-derived phases, that were primarily located in frontal, temporal and occipital gray matter areas, as well as in supratentorial neuronal projections (p < 0.001 family-wise error corrected). ALS patients with higher overall disease aggressiveness (D50 < 30 months) showed a distinct pattern of supratentorial white matter density decreases relative to patients with lower aggressiveness; no significant differences were observed for gray matter density (p < 0.001 family-wise error corrected). The application of the D50 disease progression model separates measures of disease aggressiveness from disease accumulation. It revealed a strong correlation between disease phases and in-vivo measures of cerebral structural integrity. This study underscores the proposed corticofugal spread of cerebral pathology in ALS. We recommend application of the D50 model in studies linking clinical data with neuroimaging correlates.

Project description:Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.

Dataset Information

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis.

Publications

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis.

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