Investigation of reactive astrogliosis effect on post-stroke cognitive impairment

Abstract

Background: The aim of this study is to investigate the associations between post-stroke cognitive impairment (PSCI) severity and reactive astrogliosis (RA) extent on normalized ¹⁸F-THK-5351 positron-emission tomography (PET) imaging in amyloid-negative patients with first-ever stroke.

Methods: We prospectively enrolled 63 amyloid-negative patients with first-ever stroke. Neurocognitive evaluation, MRI, ¹⁸F-THK-5351, and ¹⁸F-florbetapir PET were performed around 3 months after stroke. The ¹⁸F-THK-5351 uptake intensity was normalized using a signal distribution template to obtain the Z-SUM scores as the RA extent in the whole brain and cerebral hemisphere ipsilateral to stroke lesion. We evaluated stroke volume, leukoaraiosis, and brain atrophy on MRI. We used a comprehensive neurocognitive battery to obtain composite cognitive scores, and defined PSCI as a general cognitive function score < - 1. We analyzed the influence of Z-SUM scores on PSCI severity after adjusting for demographic, vascular, and neurodegenerative variables.

Results: Twenty-five of 63 stroke patients had PSCI. Patients with PSCI had older age, lower education, and more severe cortical atrophy and total Z-SUM scores. Total Z-SUM scores were significantly associated with general cognitive and executive functions at multiple regression models. Path analyses showed that stroke can exert cognitive influence directly by stroke itself as well as indirectly through RA, including total and ipsilateral Z-SUM scores, in patients with either right or left hemisphere stroke.

Conclusion: The patterns and intensity of ¹⁸F-THK-5351 uptake in amyloid-negative patients with first-ever stroke were associated with PSCI manifestations, which suggests that RA presents a modulating effect in PSCI development.

Keywords: PET; Post-stroke cognitive impairment; Reactive astrogliosis; Stroke.

Fig. 1

Transforming the ¹⁸F-THK-5351 SUVR maps to ¹⁸F-THK-5351 Z-score maps. Regarding a representative healthy subject (a), off-target binding of ¹⁸F-THK-5351 to the basal ganglia and thalamus was noted on the SUVR maps (b, c). After transforming SUVR maps to Z-score maps, the signals in the basal ganglia and thalamus were robustly diminished (d). Regarding a patient with right hemisphere ischemic stroke (e), ¹⁸F-THK-5351 uptake signals were increased around the stroke lesion; further, they were asymmetrically elevated in the basal ganglia and thalamus on SUVR maps (f, g). On the Z-score map, the ¹⁸F-THK-5351 signals on the bilateral basal ganglia and thalamus were markedly suppressed and the stroke-induced ¹⁸F-THK-5351 uptake was better visualized (h)

Fig. 2

Comparisons of ¹⁸F-THK-5351 uptake patterns among the SUVR map and Z-maps at multiple Z-score thresholds. A patient with a lacunar infarct at the right internal capsule (a, b) shows increased ¹⁸F-THK-5351 uptake around the stroke lesion on the SUVR maps (c, d). On the Z-maps with sequentially increasing thresholds, the ¹⁸F-THK-5351 uptake regions gradually shrink (e–h). Furthermore, the increased ¹⁸F-THK-5351 uptake might extend to the cerebral cortex without corresponding changes observed on the conventional FLAIR and DWI images

Fig. 3

The correlations of cognitive results with total Z-SUM-4 scores, the normalized ¹⁸F-THK-5351 uptake intensity. The total Z-SUM-4 score was significantly correlated with Instrumental Activities of Daily Living (IADL) score (a), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score (b), general cognitive function (c), and executive function performance (d)

Fig. 4

Path analyses of stroke effects on cognition via total or ipsilateral Z-SUM-4 scores after age, education and depressive symptoms adjustment. Stroke volume contributes significantly to cognitive function as well as total and ipsilateral Z-SUM-4 scores in patients with either left-hemispheric (a, b) or right-hemispheric (c, d) stroke. Further, ipsilateral Z-SUM-4 scores can partly mediate language influence from stroke volume in patients with left-hemispheric stroke (b). Likewise, total and ipsilateral Z-SUM-4 scores can partly mediate executive influence from stroke volume in patients with right-hemispheric stroke (c, d)