Thalamic alterations remote to infarct appear as focal iron accumulation and impact clinical outcome

Abstract

See Duering and Schmidt (doi:10.1093/awx135) for a scientific commentary on this article.Thalamic alterations have been observed in infarcts initially sparing the thalamus but interrupting thalamo-cortical or cortico-thalamic projections. We aimed at extending this knowledge by demonstrating with in vivo imaging sensitive to iron accumulation, one marker of neurodegeneration, that (i) secondary thalamic alterations are focally located in specific thalamic nuclei depending on the initial infarct location; and (ii) such secondary alterations can contribute independently to the long-term outcome. To tackle this issue, 172 patients with an infarct initially sparing the thalamus were prospectively evaluated clinically and with magnetic resonance imaging to quantify iron through R2* map at 24-72 h and at 1-year follow-up. An asymmetry index was used to compare R2* within the thalamus ipsilateral versus contralateral to infarct and we focused on the 95th percentile of R2* as a metric of high iron content. Spatial distribution within the thalamus was analysed on an average R2* map from the entire cohort. The asymmetry index of the 95th percentile within individual nuclei (medio-dorsal, pulvinar, lateral group) were compared according to the initial infarct location in simple and multiple regression analyses and using voxel-based lesion-symptom mapping. Associations between the asymmetry index of the 95th percentile and functional, cognitive and emotional outcome were calculated in multiple regression models. We showed that R2* was not modified at 24-72 h but showed heterogeneous increase at 1 year mainly within the medio-dorsal and pulvinar nuclei. The asymmetry index of the 95th percentile within the medio-dorsal nucleus was significantly associated with infarcts involving anterior areas (frontal P = 0.05, temporal P = 0.02, lenticular P = 0.01) while the asymmetry index of the 95th percentile within the pulvinar nucleus was significantly associated with infarcts involving posterior areas (parietal P = 0.046, temporal P < 0.001) independently of age, gender and infarct volume, which was confirmed by voxel-based lesion-symptom mapping. The asymmetry index of the 95th percentile within the entire thalamus at 1 year was independently associated with poor functional outcome (P = 0.04), poor cognitive outcome (P = 0.03), post-stroke anxiety (P = 0.04) and post-stroke depression (P = 0.02). We have therefore identified that iron accumulates within the thalamus ipsilateral to infarct after a delay with a focal distribution that is strongly linked to the initial infarct location (in relation with the pattern of connectivity between thalamic nuclei and cortical areas or deep nuclei), which independently contributes to functional, cognitive and emotional outcome.

Sensorimotor stroke alters hippocampo-thalamic network activity

“…It appears histologically as astrogliosis, microglial activation and neuronal death 30 – 33 . Recently, focal thalamic iron accumulation has been visualized on MRI in stroke patients with infarcts initially sparing the thalamus, which was most likely attributable to secondary degeneration as well 34 .…”

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

“…In another study that evaluates patients at 3 months after stroke, the thalamic microstructural abnormalities detected by DTI imaging correlate with lower verbal fluency performance, suggesting the secondary abnormalities in thalamus are related to cognitive dysfunction (45). A prospective cohort study by Kuchcinski and colleagues demonstrate that the secondary thalamic alteration after focal cortical injury independently contributes to poor functional, cognitive and emotional outcome (46). However, the role of secondary thalamic injury in stroke outcome remains debatable.…”

Serum neurofilament light

“…Given previous evidence for secondary neurodegeneration after acute ischemic infarcts 8,9,11,35,36 and the observed longlasting elevations of serum NfL levels 6 months post stroke, we next assessed the association between secondary neuroaxonal injury after stroke and serum NfL levels at 6 months in the DEMDAS cohort. As a quantitative measure for secondary neuroaxonal injury, we calculated the change in MD (DMD-p90) in major white matter tracts outside the infarct area between baseline and 6 months post stroke (figure 3, A and B).…”

“…4,5 Such lesions might also be reflected in circulating molecules. 6,7 Acute infarcts further induce secondary neurodegeneration outside the infarct area 8,9 including white matter tracts connected to the infarct. 10,11 Such secondary damage likely contributes to clinical outcome 8 and might also be reflected in molecules released from injured neurons.…”

“…6,7 Acute infarcts further induce secondary neurodegeneration outside the infarct area 8,9 including white matter tracts connected to the infarct. 10,11 Such secondary damage likely contributes to clinical outcome 8 and might also be reflected in molecules released from injured neurons. As such, circulating neuronal injury markers could be of interest for patient monitoring and for use in observational and interventional studies.…”