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Inflammation, CRP & new test (DTI, difussion tensor imaging) - Are white matter signal abnormalities clinically relevant? Editorial
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In this issue of Neurology, Wersching and colleagues2 used diffusion tensor imaging (DTI) to identify regions of abnormality in the white matter. They go on to relate these features to a marker of low-grade inflammation that has been associated with cerebral microstructural disintegration and impaired cognition.....Alterations to blood vessels such as changes in the artery endothelial function or thickening of the intima-media as indicated by elevations in circulating C-reactive proteins would decrease the efficiency of the blood flow and increase the likelihood of ischemic or perfusion/reperfusion injury to the white matter.
Ronald J. Killiany, PhD
From the Boston University School of Medicine, Boston, MA.
Address correspondence and reprint requests to Dr. Ronald J. Killiany, Center for Biomedical Imaging, Boston University School of Medicine, 700 Albany Street, W701, Boston, MA 02118 Killiany@bu.edu
How often have you read, "There are small scattered foci of signal abnormalities (T2 hyperintensities or increased FLAIR signal) in the cerebral white matter indicative of demyelinating disease, chronic white matter ischemia due to microvascular disease, or gliosis from an infectious/inflammatory disease process," or words just like them in your MRI reports of your elderly patients with cognitive complaints? With this information in hand, do you find yourself struggling to decide how to properly care for your patient: Is this finding clinically relevant? Is it treatable?
We have struggled since at least the early 1900s, when Otto Binswanger described encephalitis chronica progressivea to understand the etiology underlying what we all commonly see reported today on MRI as white matter signal abnormalities. Histologically, Binswanger disease has been associated with changes in the axons and their overlying myelin sheaths resulting in gliosis; this is a consequence of a regional loss or change to the blood supply to the white matter of the brain.1 However, data are scarce that support the notion that the same process could account for the more restricted findings we often see today on MRI. Up until very recently, we have relied on fluid-attenuated inversion recovery (FLAIR) MRI, in which the CSF signal is nullified, leaving the signal abnormalities bright white on the grayscale background. While this technique has improved our ability to see these features that were once referred to as unidentified bright objects, it has not helped us very much in trying to understand them.
From a research perspective, we have come to understand that there is at least a weak relationship between white matter signal abnormalities and cognition, although the jury is still out about whether and to what extent this is clinically meaningful. As we all know, the white matter of the brain is not a homogeneous entity but rather is a very heterogeneous region of pathways and tracts. Yet the methods we have traditionally used to view white matter signal abnormalities do not allow us to view these pathways and tracts. In this issue of Neurology, Wersching and colleagues2 used diffusion tensor imaging (DTI) to identify regions of abnormality in the white matter. They go on to relate these features to a marker of low-grade inflammation that has been associated with cerebral microstructural disintegration and impaired cognition.
DTI looks at the ability of polar molecules, such as water, to move in their local environment. For example, water molecules in the ventricles should be free to move in any direction; this roughly spherical movement is termed isotropic movement. At the opposite extreme, water molecules in the white matter tend to have their movement restricted by the membranes around them (axon and myelin) so that they can move relatively freely in one direction but not in others, resulting in elliptical shaped movement, referred to as anisotropic movement. Think of yourself stuck in the center island of a busy road trying to cross the street: your movement across traffic in front of you and behind you is restricted but you could likely move up and down the street in the direction of traffic. By connecting the adjacent anisotropic voxels, pathways and tracts can be inferred and disruptions to them identified.3 When compared to more conventional forms of imaging (i.e., diffusion weighted, T2-weighted alone [such as FLAIR], or T2 in combination with proton density weighted), alterations on DTI are slower to develop but much longer lasting.4 Presumably, this is a reflection of changes in the axons, loss of myelin, redundant lamination, or expansion of the extracellular spaces, rather than a change in the concentration of water in the local environment. By allowing us to visualize both pathways and pathology, DTI provides us the ability to expand vastly our understanding of the organization and functions of white matter. As Wersching and colleagues demonstrated, the associations between C-reactive protein levels and FA contrasted with the failure to find similar associations with white matter lesions in FLAIR images.
White matter is susceptible to injury in part because it is at the end of the blood supply with flow coming from either the lenticulostriate arteries or penetrating vessels. DTI appears to be superior to standard magnetic resonance techniques for demonstrating such injuries. This capability offers the prospect of clarifying the role of microvascular disease in late-life cognitive disorders. C-reactive protein levels are an indicator of coronary artery events,5 and therefore should carry some risk for cerebrovascular disease. Alterations to blood vessels such as changes in the artery endothelial function or thickening of the intima-media as indicated by elevations in circulating C-reactive proteins would decrease the efficiency of the blood flow and increase the likelihood of ischemic or perfusion/reperfusion injury to the white matter. The findings of Wersching and colleagues offer the prospect that a combination of measurements of systemic inflammation (C-reactive protein) and sensitive imaging modalities (DTI) might someday provide an assay for brain microvascular disease and provide a means for intervention.
Dr. Killiany has a clinical affiliation with Essex Neurological Associates and a research affiliation with the MRI Centers of New England; serves as the Director of the Boston University Center for Biomedical Imaging and the codirector of the Boston University School of Medicine Masters Program in Bioimaging; serves as acting site PI for the Boston University contribution to the Alzheimer's Disease Neuroimaging Initiative (U01-AG024904); and receives research support from the NIH (P01-AG000001 [Co-I], R37-AG1760901 [Co-I], and P42-ES07381 [Co-I]).
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