Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

Zhang, Jian; Zhang, Yusheng; Xing, Shihui; Liang, Zhijian; Zeng, Jinsheng

doi:10.1161/strokeaha.111.632448

Cited by 189 publications

(182 citation statements)

References 51 publications

(79 reference statements)

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“…1,37 A limitation of this study is the relatively low number of subjects within subgroups, precluding meaningful analyses on the influence of infarct location or differences between etiologic subgroups. Second, our patients might not be fully representative of a typical stroke sample in that they were relatively mildly affected.…”

Section: Figure 4 Influence Of Infarct Cavitationmentioning

confidence: 99%

Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts

et al. 2015

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Objective: To study remote effects distant from acute ischemic infarcts by measuring longitudinal changes of cortical thickness in connected brain regions as well as changes in microstructural integrity in connecting fiber tracts.Methods: Thirty-two patients (mean age 71 years) underwent a standardized protocol including multimodal MRI and clinical assessment both at stroke onset and 6 months after the event. Cortex connected to acute infarcts was identified by probabilistic diffusion tensor tractography starting from the acute lesion. Changes of cortical thickness were measured using the longitudinal stream of FreeSurfer. Microstructural damage in white matter tracts was assessed by changes of mean diffusivity. Results:We found focal cortical thinning specifically in areas connected to acute infarcts (p , 0.001). Thinning was more pronounced in regions showing a high probability of connectivity to infarcts. Microstructural damage in white matter tracts connecting acute infarcts with distant cortex significantly correlated with thickness changes in that region (r 5 20.39, p 5 0.028). There was no indication of an influence of cavitation status or infarct etiology on the observed changes in cortex and white matter.Conclusions: These findings identify secondary degeneration of connected white matter tracts and remote cortex as key features of acute ischemic infarcts. Our observations may have implications for the understanding of structural and functional reorganization after stroke. Remote cortical effects of acute infarcts critically contribute to functional reorganization after stroke and influence clinical outcome.1,2 We recently identified focal cortical thinning as a potential structural correlate of remote effects after ischemic lesions. In a small retrospective study on 9 patients with inherited small vessel disease, we showed that incident subcortical lacunes are associated with focal thinning in cortex connected to the infarct. 3,4 We attributed these findings to secondary cortical neurodegeneration following damage to the connecting subcortical fiber tracts. However, the study protocol and small sample size precluded a detailed assessment of these tracts and how changes in these tracts relate to changes in the connected cortex. Also, the results were obtained in a rare hereditary condition and were limited to a single infarct mechanism and to chronic, cavitating infarcts.In the current prospective, longitudinal study, we investigated the processes driving secondary neurodegeneration after acute infarcts. We measured changes of cortical thickness and microstructural integrity of connecting white matter tracts over a 6-month interval starting from stroke onset. We tested the following hypotheses: (1) cortical thinning in connected cortical regions is detectable within a few months after an acute infarct; (2) cortical thinning relates to *These authors contributed equally to this work.

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Section: Figure 4 Influence Of Infarct Cavitationmentioning

confidence: 99%

Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts

et al. 2015

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“…Dying of axons from a loss of neuronal cell bodies is termed Wallerian degeneration. Wallerian degeneration can be seen clinically in MRI in long axonal tracts as an early diminished diffusion of water and later as hyperintensities in T2 or FLAIR sequences, corresponding to periods of initial axon damage and then degeneration [79][80][81]. Dying axons release signals that cause reactive astrocytosis and microglial responses within days to weeks of the distant stroke [78,81].…”

Section: Relayed Stroke: Effects Of Ischemia On Distant Connected Bramentioning

confidence: 99%

“…Wallerian degeneration can be seen clinically in MRI in long axonal tracts as an early diminished diffusion of water and later as hyperintensities in T2 or FLAIR sequences, corresponding to periods of initial axon damage and then degeneration [79][80][81]. Dying axons release signals that cause reactive astrocytosis and microglial responses within days to weeks of the distant stroke [78,81]. These distant signals from a focal stroke are detected at connected sites to the stroke core, such as the contralateral cortex, substantia nigra, brain stem, and spinal cord, and include activation of the cytokines TNF-α and interleukin-6 [78].…”

Section: Relayed Stroke: Effects Of Ischemia On Distant Connected Bramentioning

confidence: 99%

“…A delayed apoptotic cell death occurs in the thalamus in experimental stroke models after cortical stroke that is distant to the thalamus [87], and similarly in the substantia nigra after striatal stroke that is distant from the substantia nigra [81]. After white matter stroke, connected cortical areas suffer a delayed damage that is seen as cortical thinning in magnetic resonance imaging [88], and as an overall brain atrophy [89].…”

Section: Relayed Stroke: Effects Of Ischemia On Distant Connected Bramentioning

confidence: 99%

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The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

Carmichael

2016

Neurotherapeutics

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Stroke not only causes initial cell death, but also a limited process of repair and recovery. As an overall biological process, stroke has been most often considered from the perspective of early phases of ischemia, how these inter-relate and lead to expansion of the infarct. However, just as the biology of later stages of stroke becomes better understood, the clinical realities of stroke indicate that it is now more a chronic disease than an acute killer. As an overall biological process, it is now more important to understand how early cell death leads to the later, limited recovery so as develop an integrative view of acute to chronic stroke. This progression from death to repair involves sequential stages of primary cell death, secondary injury events, reactive tissue progenitor responses, and formation of new neuronal circuits. This progression is radial: from the tissue that suffers the infarct secondary injury signals, including free radicals and inflammatory cytokines, radiate out from the stroke core to trigger later regenerative events. Injury and repair processes occur not just in the local stroke site, but are also triggered in the connected networks of neurons that had existed in the stroke center: damage signals are relayed throughout a brain network. From these relayed, distributed damage signals, reactive astrocytosis, inflammatory processes, and the formation of new connections occur in distant brain areas. In short, emerging data in stroke cell death studies and the development of the field of stroke neural repair now indicate a continuum in time and in space of progressive events that can be considered as the 3 Rs of stroke biology: radial, relayed, and regenerative.

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“…112 The phenomenon in which remote, but connected, brain regions may be functionally impaired after a focal ischemic lesion was initially termed 'diaschisis'. 113 Although diaschisis in principle describes a reversible functional phenomenon and does not imply morphologic changes, 114 it has become clear that reversible or irreversible histopathologic changes may develop in remote connected areas with alterations such as cellular swelling and changes in neuronal morphology.…”

Section: Snl In Remote Areas After Focal Ischemia Neuropathologymentioning

confidence: 99%

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

Baron

Yamauchi

Fujioka

et al. 2013

J Cereb Blood Flow Metab

207

208

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As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11 C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.

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Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

Cited by 189 publications

References 51 publications

Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts

Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

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