Remote changes after ischaemic infarcts: a distant target for therapy?

This scientific commentary refers to ‘Thalamic alterations remote to infarct appear as focal iron accumulation and impact clinical outcome’, by Kuchcinski et al. (doi:10.1093/brain/awx114). Ischaemic stroke was long viewed as an acute disease with sudden onset following a brain artery occlusion. This view has evolved towards a broader concept that includes long-term changes before and after the acute event, involving both chronic degenerative as well as regenerative processes. It is now well established that ischaemic infarcts also exert effects distant from the acute lesion itself, in remote, connected regions. In this issue of Brain, Kuchcinski et al. make a significant contribution to this emerging theme by demonstrating thalamic R2* alterations 1 year after a distant ischaemic infarct (Kuchcinski et al., 2017). In their longitudinal study, Kuchcinski et al. showed that the thalamic R2* signal was unaltered in the subacute phase (24–72 h after symptom onset) but was increased 1 year after the acute event, suggesting a delayed deposition of iron as a marker of neurodegeneration. R2* signal alterations were seen in specific thalamic regions depending on the location of the infarct, thus suggesting a link with the structural connectivity of the thalamus. Furthermore, these secondary and delayed thalamic alterations were independently associated with clinical outcome. The current study is not the first to demonstrate remote thalamic changes in the context of ischaemic stroke. In the 1990s, imaging studies showed thalamic atrophy (Tamura et al., 1991) and alterations of the thalamic MRI signal (Ogawa et al., 1997) following distant infarcts. Remote thalamic degeneration has also been recapitulated in experimental models (Baron et al., 2014). Nevertheless, in vivo studies in humans have been limited in terms of mechanistic insights and clinical relevance. Beyond the thalamus, remote effects of ischaemic infarcts have also been demonstrated in the cortex, in the form of functional reorganization as well as structural changes after stroke. For example, strictly subcortical ischaemic lesions were shown to induce remote cortical thinning specifically in connected cortical regions (Duering et al., 2012, 2015). By controlling for global changes in cortical thickness and taking the contralateral hemisphere as a control, these studies suggested that the structural alteration of the connected cortex was directly linked to the subcortical lesion, and not merely a global phenomenon. Microstructural alterations in the connecting fibre tracts, as revealed by diffusion tensor imaging, suggested degeneration of connecting tracts as the basis for remote cortical alterations. In a similar fashion to the current study by Kuchcinski et al., focal grey matter alteration in a remote area connected to an acute lesion is indicative of secondary neurodegeneration. Glossary Brain iron: Iron accumulates in different brain structures and at different rates as a consequence of normal ageing, but has also been associated with inflammatory, neurodegenerative, and cerebral small vessel disease. Whether iron deposition is a causative factor for brain diseases or an epiphenomenon is as yet unclear. R2* mapping: Quantitative MRI technique for the in vivo detection of iron content in tissue by estimating the R2* relaxation rate. Secondary neurodegeneration: Morphological changes to neurons in brain regions remote from (but connected to) the primary site of injury. There are several potential cellular mechanisms for secondary neurodegeneration in the thalamus (Fig. 1A). Retrograde degeneration (also sometimes inaccurately referred to as ‘dying-back’) propagates from the axonal lesion to the soma, leading to degeneration of the entire neuron. Secondary neurodegeneration may also extend beyond synapses: anterograde trans-synaptic degeneration is related to the loss of synaptic input. The death of an entire neuron as an immediate consequence of the loss of input is known to occur in settings with low wiring complexity, but seems unlikely in the thalamus. Still, a loss of synaptic input might lead to subtle changes, such as shrinkage of dendrites and cell bodies. In addition, an indirect path has been demonstrated in the cortex, where interneurons in layer I became activated after losing input and went on to induce nitric oxide-mediated apoptosis in pyramidal neurons (Koliatsos et al., 2004). Similar mechanisms involving interneurons might be at play in the thalamus (Fig. 1B). Schematic representation of potential mechanisms of secondary neurodegeneration and iron deposition. (A) Changes to a thalamic neuron following remote, ischaemic damage (red arrow) to an outgoing or incoming axon. (B) Interneurons might have an intermediary function by inducing apoptosis in neurons following loss of synaptic input. (C) A plausible source of iron is breakdown of iron-rich myelin through Wallerian degeneration of fibre tracts. By using quantitative R2* mapping, the study by Kuchcinski et al. has the potential to provide new insights at the tissue level. The R2* method represents one of many techniques for in vivo MRI assessment of iron content. Importantly, this method has been validated in post-mortem MRI studies, which showed that R2* values strongly correlated with tissue iron concentrations as assessed by mass spectrometry in prespecified grey matter regions including the thalamus (Langkammer et al., 2010). Thus, there is little doubt that the thalamic R2* alterations 1 year after the distant ischaemic infarct indeed relate to iron accumulation. In our view, two key questions have the potential to provide crucial mechanistic insight and remain open for further investigation. (i) What is the exact source of these iron deposits?; and (ii) is the observed focal iron deposition restricted to the thalamus or more widespread? Kuchcinski et al. focused on the thalamus alone. Consequently, it is possible that iron deposition is also present in other areas of the brain, such as along the entire course of white matter fibre tracts originating from the infarct. Myelin is known to contain the highest amounts of non-haem iron in brain parenchyma (Connor and Menzies, 1995). It is therefore conceivable that iron deposition is a result of anterograde (Wallerian) degeneration of axons, oligodendrocytes and myelin along entire tracts (Fig. 1C). Unfortunately, while R2* maps readily enable quantification of iron content in grey matter, this is not the case for white matter, where R2* correlated only poorly or not at all with iron content (Li et al., 2009; Langkammer et al., 2010). Thus, R2* will not allow the study of iron deposits along the entire length of affected fibre tracts. Nevertheless, on the basis of the current study plus previous studies on remote thalamic alterations after stroke, it seems reasonable to assume that there is indeed a certain degree of neurodegeneration in the thalamus. It is furthermore plausible that thalamic degeneration and iron accumulation result from multiple cellular processes. Further experimental studies are required to determine the exact mechanisms and to identify potential molecular targets, which could open up new possibilities for therapeutic interventions (Zhang et al., 2012). Currently, we can only speculate on the therapeutic potential of interfering with secondary neurodegeneration. However, an important aspect of the study presented by Kuchcinski et al. is that they established a link between secondary thalamic alterations and long-term outcome after stroke. This is in line with an MRI study on patients with spinal cord injury, which found that remote degeneration of motor pathways is related to poorer motor recovery (Freund et al., 2013). Infarct characteristics, such as lesion location, size and severity of tissue damage, typically show great variability. Because of the strong connectivity of the thalamus to the entire brain, secondary thalamic degeneration might be a common factor in determining clinical outcome and long-term recovery of stroke patients.