Hypoperfusion of the Cerebral White Matter in Multiple Sclerosis: Possible Mechanisms and Pathophysiological Significance

Abstract

Multiple sclerosis (MS) is a disease of the central nervous system characterized by patchy areas of demyelination, inflammation, axonal loss and gliosis, and a diffuse axonal degeneration throughout the so-called normal-appearing white matter (NAWM). A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces. Pathologic and imaging studies suggest that ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions), and there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS.

New Markers of Early Cardiovascular Risk in Multiple Sclerosis Patients: Oxidized-LDL Correlates with Clinical Staging

“…The recruitment and extravasation of immune cells across the activated endothelium of the BBB is considered to be a critical step in MS pathogenesis. A significant amount of cerebral vascular endothelial dysfunction has been reported in MS [24], accompanied by some degree of cerebral hypoperfusion [25]. Weinstock-Guttman et al, studying a population of 492 MS patients, concluded that serum lipid profile had modest effects on disease progression.…”

Perfusion imaging of spinal cord contusion: injury-induced blockade and partial reversal by β2-agonist treatment in rats

“…Interestingly, hypoperfusion of white matter occurs in multiple sclerosis and has been attributed to a lack of astrocytic b 2 -receptors that is associated with this condition. 5 The current study also illustrates the potential value of laser Doppler perfusion imaging in the evaluation of spinal cord injury. This modality may prove to be valuable for assessing the severity of spinal cord injury and the extent of surrounding tissue involvement.…”

Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis: The Hydrostatic-Immune Paradigm and the Flow Cytometry as a Diagnostic Tool

“…On a more macroscopic scale, MS has been associated with diffuse brain hypoperfusion [16] and decreased cerebral metabolism [17] even in the initial stages of the disease [18]. Using dynamic susceptibility contrast-enhanced magnetic resonance imaging, Law et al [19] found significantly decreased cerebral blood flow (CBF) and significantly prolonged mean transit time throughout the normal appearing white matter (NAWM) in patients with relapsing-remitting MS. Adhya et al [20] also found significantly decreased CBF and cerebral blood volume (CBV) in NAWM regions of patients with either relapsingremitting or primary progressive MS compared with healthy subjects.…”

“…These findings indicate that globally decreased white matter perfusion may be common in all subtypes of the disease [16]. Blood supply to the grey matter appears to be also compromised [21] either by the same mechanism affecting white matter or as a result of a dissociation between the cerebral cortex and subcortical structures due to the white matter damage.…”

“…In MS white matter lesions and NAWM, astrocytes were found to be deficient in β2-adrenergic receptors [26]. Decreased cAMP formation due to impaired β2 signaling may lead to vasoconstriction trough several mechanisms [16], implying a key role for astrocyte dysfunction in MS hypoperfusion. The cause of astrocyte dysfunction has not been elucidated yet, but spatial correlation of lesions and blood vessels may provide a clue.…”