Mapping anterograde and retrograde degeneration af
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神经科学杂志 2005年第2期
Tools to quantify secondary degeneration after stroke and monitor effects of intervention
Keywords: Diffusion tensor imaging; imaging; stroke
In this issue, two original articles from highly experienced groups report on the use of diffusion tensor imaging (DTI) to map the dynamics of secondary degeneration after stroke (see pp 200–5 and 266–8). Thomalla et al1 monitored in two patients the time course of Wallerian degeneration (WD) of the pyramidal tract following striatocapsular stroke. DTI was obtained on three occasions from the subacute into the chronic stage. They found a progressive decrease of the fractional anisotropy (FA) with an increase in mean diffusivity (MD) in the pyramidal tract at the level of the cerebral peduncle, reflecting the changes expected in WD—a progressive disintegration of fibre structure. Hervé et al2 serially studied nine patients from 1 week to 6 months following MCA territory stroke, focusing on the ipsilateral thalamus. They found significant increases in MD from 1 month onward, without parallel changes in FA, presumably reflecting a progressive loss of neurones and/or glial cells. These changes in thalamic MD without changes in FA indicate that within complex multi-nucleated grey matter structures devoid of large fibre bundles such as the thalamus, changes in FA should not be anticipated while loss of organised cellular arrangements will translate as increased MD. These findings likely reflect retrograde degeneration of the thalamo-cortical neurones secondary to fibre damage, known to translate in its early stage as hypometabolism and microglial activation in positron emission tomography (PET) studies using the tracers 18FDG and 11C-PK11195, respectively,3,4 and in its late stage as reduced thalamic volume on structural imaging (also observed by Hervé et al).
Fractional anisotropy—the degree to which diffusion is anisotropic—reflects the parallel arrangement of fibres, so is used as an index of integrity for any particular bundle. However, this method is limited because to obtain quantitative values for a given fibre tract, a region of interest must be positioned within the bundle based on a priori knowledge. A sophisticated application of DTI referred to as tractography applies mathematical modelling to three dimensional anisotropy data to map the trajectory of a fibre in both directions from a chosen "seed" point in the bundle. Among the various tractography techniques, one particularly promising approach takes into account all possible directions rather than just the main eigenvector, which in turn allows the probabilistic mapping of connections between gray matter areas, including cortical to deep nuclei and vice versa.5 Exquisite mapping of the thalamo-cortical connection systems has been obtained using this method; the application to stroke is eagerly awaited.
But what purposes will the mapping of fibre and cell degeneration after stroke serve? Whilst studies such as these are just the beginnings, several potential uses of this new approach are emerging. Quantifying with FA the degree of damage to a single well identified tract such as the pyramidal may, in conjunction with functional imaging such as fMRI, help to understand the pathophysiological mechanisms underlying recovery. For instance, knowing this quantitative index of damage could allow one to derive in quantitative terms the amount of recovery that can be ascribed to adaptive plasticity.6 Also, estimating the number of fibres connecting two or more cortical centres may help to determine the occurrence of functional versus anatomical disconnection. However, because the effects measured with DTI only reflect secondary effects of stroke that develop as patients recover, no obvious direct clinical implication of these studies has emerged thus far, and accordingly Hervé et al2 found no significant correlation between the changes they measured in the ipsilateral thalamus and concomitant clinical scores or changes thereof. Although these remote degeneration effects might therefore be epiphenomenal, one may envisage that they may impede or slow down recovery if they were to impact on intact but inter-connected structures for example. Whilst arguably a long shot, one could in turn wonder whether arresting or even preventing secondary degeneration could be worthwhile – although by doing so one might perhaps worsen rather than enhance outcome if the degeneration served to re-set the local excitatory/inhibitory balance.7 More work is obviously needed to address these issues but we now at last have a tool at our disposal to quantify secondary degeneration after stroke and to monitor any effect of intervention in parallel with clinical function.
REFERENCES
Thomalla G, Glauche V, Weiller C, et al. Time Course of Wallerian Degeneration after Ischemic Stroke Revealed by Diffusion Tensor Imaging. J Neurol Neurosurg Psychiatry 2004;75:266–8.
Hervé D, Molko N, Pappata S, et al. Longitudinal thalamic diffusion changes after middle cerebral artery infarcts. J Neurol Neurosurg Psychiatry 2004;75:200–5.
Baron JC. Depression of energy metabolism in distant brain structures: studies with positron emission tomography in stroke patients. Semin Neurol 1989;9:281–5.
Pappata S, Levasseur M, Gunn RN, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and 11C-PK11,195. Neurology 2000;55:1052–4.
Behrens TE, Johansen-Berg H, Woolrich MW, et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat Neurosci 2003;6:750–7.
Calautti C, Baron JC. Functional imaging of motor recovery after stroke: a review. Stroke 2003;34:1553–66.
Schallert T, Jones TA, Lindner MD. Multilevel transneuronal degeneration after brain damage: behavioral events and effects of anticonvulsant gamma-aminobutyric acid-related drugs. Stroke 1990;21 (Suppl III) :143–6.(J-C Baron)
Keywords: Diffusion tensor imaging; imaging; stroke
In this issue, two original articles from highly experienced groups report on the use of diffusion tensor imaging (DTI) to map the dynamics of secondary degeneration after stroke (see pp 200–5 and 266–8). Thomalla et al1 monitored in two patients the time course of Wallerian degeneration (WD) of the pyramidal tract following striatocapsular stroke. DTI was obtained on three occasions from the subacute into the chronic stage. They found a progressive decrease of the fractional anisotropy (FA) with an increase in mean diffusivity (MD) in the pyramidal tract at the level of the cerebral peduncle, reflecting the changes expected in WD—a progressive disintegration of fibre structure. Hervé et al2 serially studied nine patients from 1 week to 6 months following MCA territory stroke, focusing on the ipsilateral thalamus. They found significant increases in MD from 1 month onward, without parallel changes in FA, presumably reflecting a progressive loss of neurones and/or glial cells. These changes in thalamic MD without changes in FA indicate that within complex multi-nucleated grey matter structures devoid of large fibre bundles such as the thalamus, changes in FA should not be anticipated while loss of organised cellular arrangements will translate as increased MD. These findings likely reflect retrograde degeneration of the thalamo-cortical neurones secondary to fibre damage, known to translate in its early stage as hypometabolism and microglial activation in positron emission tomography (PET) studies using the tracers 18FDG and 11C-PK11195, respectively,3,4 and in its late stage as reduced thalamic volume on structural imaging (also observed by Hervé et al).
Fractional anisotropy—the degree to which diffusion is anisotropic—reflects the parallel arrangement of fibres, so is used as an index of integrity for any particular bundle. However, this method is limited because to obtain quantitative values for a given fibre tract, a region of interest must be positioned within the bundle based on a priori knowledge. A sophisticated application of DTI referred to as tractography applies mathematical modelling to three dimensional anisotropy data to map the trajectory of a fibre in both directions from a chosen "seed" point in the bundle. Among the various tractography techniques, one particularly promising approach takes into account all possible directions rather than just the main eigenvector, which in turn allows the probabilistic mapping of connections between gray matter areas, including cortical to deep nuclei and vice versa.5 Exquisite mapping of the thalamo-cortical connection systems has been obtained using this method; the application to stroke is eagerly awaited.
But what purposes will the mapping of fibre and cell degeneration after stroke serve? Whilst studies such as these are just the beginnings, several potential uses of this new approach are emerging. Quantifying with FA the degree of damage to a single well identified tract such as the pyramidal may, in conjunction with functional imaging such as fMRI, help to understand the pathophysiological mechanisms underlying recovery. For instance, knowing this quantitative index of damage could allow one to derive in quantitative terms the amount of recovery that can be ascribed to adaptive plasticity.6 Also, estimating the number of fibres connecting two or more cortical centres may help to determine the occurrence of functional versus anatomical disconnection. However, because the effects measured with DTI only reflect secondary effects of stroke that develop as patients recover, no obvious direct clinical implication of these studies has emerged thus far, and accordingly Hervé et al2 found no significant correlation between the changes they measured in the ipsilateral thalamus and concomitant clinical scores or changes thereof. Although these remote degeneration effects might therefore be epiphenomenal, one may envisage that they may impede or slow down recovery if they were to impact on intact but inter-connected structures for example. Whilst arguably a long shot, one could in turn wonder whether arresting or even preventing secondary degeneration could be worthwhile – although by doing so one might perhaps worsen rather than enhance outcome if the degeneration served to re-set the local excitatory/inhibitory balance.7 More work is obviously needed to address these issues but we now at last have a tool at our disposal to quantify secondary degeneration after stroke and to monitor any effect of intervention in parallel with clinical function.
REFERENCES
Thomalla G, Glauche V, Weiller C, et al. Time Course of Wallerian Degeneration after Ischemic Stroke Revealed by Diffusion Tensor Imaging. J Neurol Neurosurg Psychiatry 2004;75:266–8.
Hervé D, Molko N, Pappata S, et al. Longitudinal thalamic diffusion changes after middle cerebral artery infarcts. J Neurol Neurosurg Psychiatry 2004;75:200–5.
Baron JC. Depression of energy metabolism in distant brain structures: studies with positron emission tomography in stroke patients. Semin Neurol 1989;9:281–5.
Pappata S, Levasseur M, Gunn RN, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and 11C-PK11,195. Neurology 2000;55:1052–4.
Behrens TE, Johansen-Berg H, Woolrich MW, et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat Neurosci 2003;6:750–7.
Calautti C, Baron JC. Functional imaging of motor recovery after stroke: a review. Stroke 2003;34:1553–66.
Schallert T, Jones TA, Lindner MD. Multilevel transneuronal degeneration after brain damage: behavioral events and effects of anticonvulsant gamma-aminobutyric acid-related drugs. Stroke 1990;21 (Suppl III) :143–6.(J-C Baron)