Decreasing myelin density reflected increasing white matter pathology in Alzheimer's disease—a neuropathological study

Sjöbeck, Martin; Haglund, Mattias; Englund, Elisabet

doi:10.1002/gps.1384

Cited by 94 publications

(88 citation statements)

References 25 publications

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“…MRI studies in patients with MS revealed selective and progressive hippocampal atrophy localized initially to the CA1 subregion (29), which may contribute, among other factors, to cognitive impairment that occurs in many people with MS (30). Axonal degeneration, apoptosis of oligodendrocytes, myelin loss, and hippocampal atrophy are also described in chronic ischemic leukoencephalopathy and Alzheimer's disease (31)(32)(33), which are disorders that are also associated with reactive astrocytes expressing ET-1 immunoreactivity (14) and a global reduced CBF.…”

Section: Discussionmentioning

confidence: 99%

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

D’haeseleer

Beelen

Fierens³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

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Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.M ultiple sclerosis (MS) is a poorly understood chronic disorder of the CNS, characterized by focal inflammatory demyelinating lesions and degenerative processes (1). Immune responses play a crucial role in the pathogenesis of focal lesions that constitute the pathological substrate for relapses. However, the underlying mechanism of the progressive degeneration of axons, which is the primary determinant of long-term disability in MS, is not clear (2), and treatment is lacking.A number of studies found that cerebral blood flow (CBF) is globally impaired in early diagnosed relapsing-remitting MS and primary progressive MS, indicating that it is an integral part of the disease that is already present at the time of diagnosis (3-5). Animal studies have shown that chronic hypoperfusion of the brain can lead to neurodegenerative changes, including axonal degeneration (6).The underlying mechanism of reduced CBF in MS is unknown. Plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) (7) were found to be elevated in patients with MS (8), and this was associated with alterations of extraocular blood flow (9). The reason for the increase in ET-1 levels in MS was unclear, and the findings have not received much attention. We hypothesized that ET-1 might play a role in reducing CBF in MS. ResultsInternal Jugular Vein ET-1 Levels. Individuals with critical illness and systemic conditions known to be associated with increased levels of ET-1 were excluded (10). Ten subjects with MS according to the revised McDonald criteria (11) and 10 matched control subjects were included. Patients with MS were autonomously seeking treatment at the department of cardiovascular and thoracic surgery of Onze-Lieve-Vrouw Ziekenhuis Aalst for so-c...

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Section: Discussionmentioning

confidence: 99%

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

D’haeseleer

Beelen

Fierens³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Reports of pathological white matter changes have been documented in at least 50% of patients with AD [18]. Pathological white matter changes include decreased myelin density [74], decreased myelin basic protein [88], loss of oligodendrocytes [75] and microgila activation [37]. It has been suggested that the loss of oligodendrocytes and myelin damage in AD is due to increased vulnerability of later myelinating regions [5,6,65].…”

Section: White Matter Damage In Ad/mci and Diffusion Tensor Imagingmentioning

confidence: 99%

“…Thus, one would predict increased mean diffusivity and isotropic diffusion (decreased FA) in the white matter of patients with AD because of the degeneration of myelinated tracts due to damage to myelin and oligodendrocytes [74,75,88]. However, these expectations are rather simplistic, given the complexity of white matter architecture.…”

Section: White Matter Damage In Ad/mci and Diffusion Tensor Imagingmentioning

confidence: 99%

Diffusion Tensor Imaging in Alzheimer’s Disease and Mild Cognitive Impairment

Stebbins

Murphy

2009

Behavioural Neurology

193

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Abstract. Structural magnetic resonance imaging (MRI) studies of Alzheimer's disease and mild cognitive impairment (MCI) have focused on the hippocampus and entorhinal cortex; gray matter structures in the medial temporal lobe. Few studies have investigated the integrity of white matter in patients with AD or MCI. Diffusion tensor imaging (DTI) is a MRI technique that allows for the interrogation of the microstructural integrity of white matter. Based on increases in translational diffusion (mean diffusivity: MD) and decreases directional diffusion (fractional anisotropy: FA) damage to white matter can be assessed. Studies have identified regions of increased MD and decreased FA in patients with AD and MCI in all lobes of the brain, as well as medial temporal lobe structures including the hippocampus, entorhinal cortex and parahippocampal white matter. The pattern of white matter integrity disruption tends to follow an anterior to posterior gradient with greater damage noted in posterior regions in AD and MCI. Recent studies have exploited inter-voxel directional similarities to develop models of white matter pathways, and have used these models to assess the integrity of inter-cerebral connections. Particular focus has been applied to the parahippocampal white matter (including the perforant path) and the posterior cingulum. Although many studies have found DTI indicators of impaired white matter in AD and MCI, other studies have failed to detect any differences in MD or FA between the groups, demonstrating the need for large replicative studies. DTI is an evolving technique and advances in its application ought to provide new insights into AD and MCI.

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“…Slides were processed for LFB (luxal fast blue). LFB staining was performed to assess the myelin formation in brain tissue [3].…”

Section: Histological Experimentsmentioning

confidence: 99%

“…Histological experiments can provide high-resolution images of a wide range of specific stains in the brain tissue such as haematoxylin and eosin, neural cell adhesion molecule [1], glial fibrillary acidic protein [2] and luxal fast blue [3]. However, these methods are destructive and provide only two-dimensional (2D) images, and three-dimensional (3D) information is difficult to obtain.…”

mentioning

confidence: 99%

Ex vivo imaging of mouse brain using micro-CT with non-ionic iodinated contrast agent: a comparison with myelin staining

Saito

Murase²

2012

The British Journal of Radiology

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Objective: We investigated the use of micro-CT with contrast agent for the noninvasive characterisation of fixed mouse brain tissue specimens as a means to differentiate between grey and white matter. Methods: Nine mice were divided into two groups for micro-CT (n56) and myelin staining (n53) experiments. Six mice underwent in vivo micro-CT and were then prepared for brain specimens by transcardiac perfusion with paraformaldehyde. The six mouse brains were soaked in two different concentrations of non-ionic iodinated contrast agents (60 and 150 mg ml 21 ). Immersion times used for each concentration of iodine were for 3, 7 and 14 days. Three-dimensional ex vivo micro-CT images were acquired with a resolution of 39 mm 3 to create isotropic images. The other three mice were stained for evaluation of the myelin structure. Results: Soaking the brains in non-ionic iodinated contrast agent resulted in clear differences in signal between the grey matter, the white matter and the ventricular spaces. The 150 mg ml 21 contrast agent solution yielded images with better contrast-tonoise ratio (CNR) than 60 mg ml 21 iodine contrast agent solution. 14 days of soaking yielded images with better CNR than 3 and 7 days. The CT contrast of grey and white matter derived from the iodine-soaked fixed brains was strongly related to tissue myelin. Conclusion:The present study demonstrated that micro-CT can be used to detect the mouse brain myelin structure at 3, 7 and 14 days after fixation using a CT contrast agent.

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Decreasing myelin density reflected increasing white matter pathology in Alzheimer's disease—a neuropathological study

Cited by 94 publications

References 25 publications

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

Diffusion Tensor Imaging in Alzheimer’s Disease and Mild Cognitive Impairment

Ex vivo imaging of mouse brain using micro-CT with non-ionic iodinated contrast agent: a comparison with myelin staining

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