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In-vivo Detection of Remote Neurodegeneration within Thalamic Nuclei after Stroke Using Iron Quantification with R2* Mapping

Grégory Kuchcinski¹, Fanny Munsch², Renaud Lopes¹, Jason Su³, Antoine Bigourdan², Brian K. Rutt³, Vincent Dousset², Igor Sibon⁴, and Thomas Tourdias²

¹Neuroradiology, Univ. Lille, CHU Lille, Lille, France, ²Neuroimagerie diagnostique et thérapeutique, Université de Bordeaux, CHU de Bordeaux, France, ³Richard M. Lucas Center for Imaging Radiology Department, Stanford University, United States, ⁴Unité neurovasculaire, Université de Bordeaux, CHU de Bordeaux, France

Synopsis

In stroke patients, remote thalamic alterations including iron deposition have been reported and attributed to the disruption of cortico-thalamic projections. Nevertheless, secondary thalamic degeneration has never been quantified so far in humans at the nucleus scale and its clinical impact is unknown. By using R2* mapping, we demonstrated (i) that iron accumulates with a focal distribution especially within the medio-dorsal nucleus and the pulvinar, (ii) that such focal thalamic iron accumulation is strongly linked to the initial stroke location, consistent with the known connectivity between thalamic nuclei and cortico-subcortical areas and (iii) is significantly impacting specific cognitive and emotional functions.

Introduction

In stroke patients, remote thalamic alterations have been reported and attributed to the disruption of cortico-thalamic projections.^1-4 However, the thalamus is composed of several nuclei,⁵ each nucleus having its own connectivity pattern^6,7 and driving specific functions.⁸ Individual thalamic nuclei should be differentially affected by secondary degeneration depending on the initial stroke location. Nevertheless, secondary thalamic degeneration has never been quantified so far in humans at the nucleus scale. The aim of the study was (i) to demonstrate regional accumulation of iron as quantified by R2* in specific thalamic nuclei in stroke patients and (ii) to demonstrate that it represents secondary damages in direct relation with the location of the initial stroke and (iii) that it is responsible for specific cognitive and emotional impairment.

Methods

One hundred and seventy-two patients with a stroke sparing the thalamus were prospectively assessed at 24-72 hours and 1 year with MRI on a 3T scanner. The MR protocol included a 2D multi-echo fast gradient-echo (FGRE) sequence with 8 echo times (4.3, 8.7, 13.0, 17.4, 21.7, 26.1, 30.5 and 34.8ms) allowing R2* mapping.⁹ R2* values were measured within the entire thalamus and within the medio-dorsal nucleus and the pulvinar using 3D-atlas-driven regions-of-interest.^10,11 First, an asymmetry index (AI) was used to compare R2* values within the thalamus ipsilateral versus contralateral to stroke. The spatial distribution of iron accumulation was analyzed on an average R2* map.¹² Then, to demonstrate the relationship between focal iron accumulation in specific nuclei and initial stroke location, AI within the medio-dorsal nucleus and the pulvinar were compared against the involvement or not of the different cortical locations and deep nuclei in univariate and multivariate analyses. We also built maps of stroke location responsible for specific iron accumulation in the medio-dorsal or in the pulvinar using an adaptation of the voxel-based symptom-lesion mapping (VLSM) method.^13,14 Finally, we calculated with multivariate regression models the associations between iron accumulation measured within the entire thalamus or within specific thalamus nuclei and functional outcome evaluated by the modified Rankin scale at 1 year, cognitive outcome evaluated by the Montreal Cognitive Assessment (MoCA) score at 1 year¹⁵ and emotional outcome evaluated by the Hospital Anxiety and Depression scale at 1 year.¹⁶

Results

R2* in the entire thalamus ipsilateral to stroke was not modified at 24-72 hours but showed heterogeneous increase at 1 year especially within the medio-dorsal nucleus and the pulvinar (Fig 1 and 2). High AI within the medio-dorsal nucleus was significantly associated with anterior stroke location (frontal p=0.05, temporal p=0.02, lenticular p=0.01) while high AI within the pulvinar was significantly associated with posterior stroke location (parietal p=0.046, temporal p<.001) independently of age, gender and stroke volume, which was confirmed on VLSM maps (Fig 3). A high AI in the entire thalamus at 1 year was independently associated with a poor cognitive outcome defined by the MoCA score in patients with left-hemispheric stroke (adjusted OR=6.48, 95%CI=1.27-32.9, p=0.02), with post-stroke anxiety (adjusted OR= 2.23, 95%CI=1.04-4.79, p=0.04) and post-stroke depression (adjusted OR= 2.77, 95%CI, 1.14-6.72, p=0.02). At the nucleus level, a high AI in the pulvinar was associated with a specific alteration of the visuospatial MoCA subscore (OR=2.17, 95%CI =0.99-4.63, p=0.055) and with post-stroke anxiety in patients with right-hemispheric stroke (OR=3.36, 95%CI=1.16-9.69, p=0.03).A high AI in the medio-dorsal nucleus tended to be associated with a specific alteration of the recall MoCA subscore in patients with left-hemispheric stroke (OR=3.60, 95%CI=0.68-19.2, p=0.13) and with post-stroke depression in patients with right-hemispheric stroke (OR=5.57, 95%CI=1.35-22.9, p=0.02).

Discussion

R2* mapping is a suitable method to demonstrate and quantify secondary remote neurodegeneration after stroke at the scale of the thalamic nucleus. Iron accumulates in the thalamus ipsilateral to stroke after a delay, with a focal distribution especially within the medio-dorsal nucleus and the pulvinar, which is strongly linked to the initial stroke location, consistently with the known connectivity pattern between each thalamic nucleus and cortico-subcortical areas. Such remote thalamic neurodegenerative lesions were independently associated with a poor cognitive and emotional outcome.

Conclusion

Remote thalamic neurodegeneration can be quantified in vivo with R2* mapping in stroke patients. The potential impact of these secondary lesions on cognitive and emotional outcome needs to be confirmed in larger longitudinal studies. This secondary neurodegenerative stream is a potential therapeutic target for neuronal protection after ischemic stroke.

Acknowledgements

No acknowledgement found.

References

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Figures

Figure 1: Illustrative case of focal iron accumulation within the medio-dorsal nucleus. A 41-year old woman with a right middle cerebral artery stroke, involving the frontal, parietal and insular cortices and the deep nuclei at initial DWI (A). The initial R2* map showed homogeneous and symmetric thalami, without any iron accumulation (B). A focal iron accumulation in the medio-dorsal nucleus ipsilateral to stroke appeared on the final R2* map (arrow, C). This focal iron accumulation was also well identified on the final raw T2* sequence with increasing TE values (8.7, 17.4 and 26.1 ms) (arrows, D-F).

Figure 2: (A) Average map of R2* at final MR imaging. (B) Enlarged view of the average R2* map (top) and atlas from the thalamic nuclei (bottom) projected onto a white-matter-nulled MPRAGE template within the MNI152 space. High R2* values are visualized in projection of the medio-dorsal nucleus (arrow) and in projection of the pulvinar (arrowhead) in stroke side compared to the contralateral side.

Figure 3: Adaptation of voxel-based lesion-symptom mapping (VLSM) visualizing the impact of stroke location on iron accumulation within the medio-dorsal nucleus (A and B) and within the pulvinar (C and D) at 1 year post stroke. The color range indicates Z-scores resulting from Brunner–Menzel testing. Lower Z-scores (red) indicate brain regions associated with higher iron accumulation. (A) VLSM maps of stroke locations associated with iron accumulation in the medio-dorsal nucleus and in the pulvinar not corrected for multiple comparisons (A and B, respectively) and after false discovery rate at p=0.05 (C and D, respectively).

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)

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