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

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 longterm 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. 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). 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 BRAIN 2017: 140; 1818–1828 | 1818