Immunohistochemical study of vascular injury in acute multiple sclerosis.

Wakefield, Andrew J.; More, L; Difford, John; McLaughlin, James E.

doi:10.1136/jcp.47.2.129

Cited by 111 publications

(94 citation statements)

References 19 publications

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“…Recently it was shown that hypoxia-like tissue injury is an important pathogenic mechanism in lesion formation in a subtype of multiple sclerosis and virus encephalitis patients (43). This process is associated in part with damage and thrombotic occlusion of microvessels (44). Data on p75TNFR expression in such lesions, however, are still missing.…”

Section: Discussionmentioning

confidence: 99%

Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice

Akassoglou

Douni

Bauer

et al. 2003

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

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Tumor necrosis factor (TNF) is up-regulated in a variety of central nervous system (CNS) diseases with diverse etiology and pathologic manifestation. TNF mediates multiple biological activities through two membrane receptors, the p55 and p75 TNF receptors (TNFRs). We have shown previously that human transmembrane TNF (tmTNF)͞p55TNFR signaling in transgenic mice triggers oligodendrocyte apoptosis, endothelial cell activation, parenchymal inflammation, and primary demyelinating lesions similar to those of acute multiple sclerosis. To address the role of the p75TNFR in the CNS, we have generated ''humanized'' mice that express human tmTNF in astrocytes and a physiologically regulated human p75TNFR transgene, in the absence of the endogenous (murine) p55TNFR. Human tmTNF͞p75TNFR transgenic mice develop CNS vascular pathology, characterized by endothelial cell activation, meningeal inflammation, and vessel fibrosis. There is no evidence of oligodendrocyte apoptosis or primary demyelination in these mice. Late in disease, vasculitis can result in vessel occlusion and secondary, multifocal CNS ischemic injury. These results identify a proinflammatory role for the p75TNFR at the level of the CNS vascular endothelium, which correlates with the expression pattern of this receptor in the CNS, and indicate that the differential expression patterns of the two TNFRs within the CNS play a significant role in shaping the outcome of TNF signaling during neuroimmune interactions.

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Section: Discussionmentioning

confidence: 99%

Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice

Akassoglou

Douni

Bauer

et al. 2003

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

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“…This is in line with the estimates of prevalence of cognitive deficits in MS that range from 40 to 65%, with higher frequency in the chronic progressive clinical subtype (Heaton et al, 1985;Rao et al, 1991a). An ischemic component has long been acknowledged in histological studies of MS (Wakefield et al, 1994). Indeed, several mechanisms may lead to hypoxia-like tissue injury in MS. Cytotoxic T cells may recognize their antigen on endothelial cells and Figure 1 Scatter plot of the correlation between the mean deep gray matter (GM) CBF expressed in mL/100 g per min versus the mean Rey Complex Figure Test (RCFT) Z-score in patients with RR-MS (J) and in patients with PP-MS (~).…”

Section: Discussionmentioning

confidence: 99%

“…During inflammation, vascular dysfunction and local production of toxic metabolites may lead to defective microcirculation and subsequent ischemia, contributing to clinical manifestations (Wakefield et al, 1994). The assessment of cerebral hemodynamics has been made possible through MRI by using dynamic susceptibility contrast (DSC)-enhanced T2*-weighted MRI (Ostergaard et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Perfusion Magnetic Resonance Imaging Correlates of Neuropsychological Impairment in Multiple Sclerosis

Inglese

Adhya

Johnson

et al. 2007

J Cereb Blood Flow Metab

105

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Although cognitive impairment is common in multiple sclerosis (MS), its pathophysiology is still poorly understood. Abnormalities of cerebral blood flow (CBF) have long been acknowledged in MS and advances in perfusion magnetic resonance imaging (MRI) allow for their assessment in vivo. We investigated the relationship between regional perfusion changes and neuropsychological (NP) dysfunctions in patients with relapsing-remitting and primary-progressive MS. Absolute CBF, cerebral blood volume (CBV) and mean transit time were measured in 32 MS patients and 11 healthy controls using dynamic susceptibility contrast-enhanced T2*-weighted MRI. A comprehensive NP test battery was administered to all patients. A mixed model analysis of covariance was performed for group comparisons in terms of perfusion measures in normal-appearing white matter (NAWM) and deep gray matter (GM). Pearson's correlations were used to describe the association of perfusion metrics with NP Z-scores. CBF and CBV values were significantly decreased in both NAWM and deep GM in MS patients compared with controls (P = 0.01). In all patients, deep GM CBF was significantly associated with Rey Complex Figure Test (RCFT)-Copy (r = 0.5; P = 0.001) and deep GM CBV and NAWM CBV were significantly associated with Color-Word Interference Inhibition Switching test (D-KEFSIS) (r = 0.4; P = 0.008 and r = 0.4; P = 0.02). However, the only associations that remained significant after Bonferroni correction were between deep GM CBF and RCFT-Copy (P = 0.006), and deep GM CBV and D-KEFSIS (P = 0.04). Our results suggest a role for tissue perfusion impairment in NP dysfunction in MS. Large-scale studies are needed to characterize better this association.

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“…On the other hand, early vascular endothelial cell activation was identified prior to cerebral parenchymal reaction and demyelination [55], which, in combination with discrete microglial activation and perivascular cellular infiltrates, is a frequent finding in postmortem tissue of MS patients [56]. Microglial activation coincided with abnormal endothelial tight junctions in active lesions and normal appearing white matter, leading to putatively open junctions in microscopically inflamed vessels [57].…”

Section: Pathophysiological Considerationsmentioning

confidence: 99%

Cerebral blood perfusion changes in multiple sclerosis

Wuerfel

Paul

Zipp

2007

Journal of the Neurological Sciences

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| The proximity of immune cell aggregations to the vasculature is a hallmark of multiple sclerosis. Furthermore, it is widely accepted that inflammation is able to modulate the microcirculation. Until recently, the detection of cerebral blood perfusion changes was technically challenging, and perfusion studies in multiple sclerosis patients yielded contradictory results. However, new developments in fast magnetic resonance imaging have enabled us to image the cerebral hemodynamics based on the dynamic tracking of a bolus of paramagnetic contrast agents (dynamic susceptibility contrast). This review discusses the technical principles, possible pitfalls, and potential for absolute quantification of cerebral blood volume and flow in a clinical setting. It also outlines recent findings on inflammation associated perfusion changes, which are inseparable from pathological considerations in multiple sclerosis.

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Immunohistochemical study of vascular injury in acute multiple sclerosis.

Cited by 111 publications

References 19 publications

Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice

Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice

Perfusion Magnetic Resonance Imaging Correlates of Neuropsychological Impairment in Multiple Sclerosis

Cerebral blood perfusion changes in multiple sclerosis

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