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Regional gray matter atrophy mediates white matter hyperintensity-induced cognitive decline following carbon monoxide poisoning1The first hospital of Lanzhou university, Lanzhou, China
Synopsis
Keywords: Gray Matter, Dementia
Motivation: To reveal the underlying neuroimaging pathology mechanisms of cognitive impairment in patients with delayed neurologic sequelae (DNS) following carbon monoxide (CO) poisoning.
Goal(s): To investigate the relationship among white matter hyperintensities (WMH), gray matter (GM) volume and cortical thickness alteration, and cognitive impairment severities in patients with DNS following CO poisoning.
Approach: Clinical retrospective observational study
Results: The DNS patients with dementia (DNS-D) group showed more severe GM atrophy and higher WMH load than those with mild cognitive impairment (DNS-MCI) group. Reduced GM volume in 16 subregions of the bilateral prefrontal, left occipital, bilateral temporal, and cerebellar regions mediated the WMH-induced cognitive decline.
Impact: Using the neuroimaging methods to explore the pathophysiological mechanism of DNS with cognitive impairment could provide a theoretical basis for exploring new therapeutic approaches. Our results provide preliminary evidence that the role of regional GM atrophy in WMH-induced cognitive decline.
Introduction
Cognitive decline is a common symptom in patients with delayed neurologic sequelae (DNS) following carbon monoxide (CO) poisoning, with severities ranging from dementia to mild cognitive impairment. Currently, the underlying neuropathology mechanisms of cognitive impairment in patients with DNS are still uncertain. Diffuse white matter hyperintensity (WMH) in the centrum semiovale area on T2-weight images is a typical imaging finding for diagnosing DNS [1]. It is widely believed that WMH lesions were associated with the cognitive decline of patients with DNS [2-5]. Using voxel-based morphometry (VBM) [6] and surface-based morphometry (SBM) analysis [7], we previously found significantly reduced gray matter (GM) volume in some subregions of the limbic lobes and significantly thinner cortical thickness in the bilateral cerebral hemisphere in patients with DNS compared with those without DNS. Moreover, some regional GM atrophy was related to their cognitive impairment severities. As a mediating factor, regional GM atrophy contributes to cognitive decline in various populations with WMH, such as aging, Alzheimer’s disease or vascular dementia have been reported in previous studies [8-11]. However, a study on the relationship among WMH load, GM structural alteration, and cognitive impairment is still lacking.Methods
Here, we aimed to investigate the GM volume and cortical thickness in 33 DNS patients with dementia (DNS-D), 24 DNS patients with mild cognitive impairment (DNS-MCI), and 51 healthy controls. The GM structural alteration (analyzing by a battery of methods including voxel-based, deformation-based, surface-based, and Brainnetome [BN] atlas-based) and WMH load were compared among the groups. The role of the altered GM structure in WMH-induced cognitive decline was investigated using mediation analyses. Last, we further conducted a verification analysis using the automated anatomical labeling 3 atlas to validate the reproducibility of the main results.Results
Both DNS groups showed widespread GM atrophy (reduced GM volume and cortical thickness) in the bilateral cerebral cortical, subcortical nuclei and cerebellum, and the DNS-D group showed more extensive and severe GM atrophy (false discovery rate [FDR]-corrected P < 0.05) (Fig. 1 and 2). Significantly decreased GM volume, mostly in the frontal-occipital-temporal region and cerebellum (FDR-corrected P < 0.05), and increased WMH burden (P < 0.05) (Fig. 3) were identified in patients with DNS-D compared with those DNS-MCI. Most importantly, regional GM atrophy in 16 subregions of the bilateral prefrontal, left occipital, bilateral temporal, and cerebellar regions mediated the relationship between WMH and cognitive decline (P < 0.05) (Fig. 4). The atlas-based analysis showed better performance than that of other methods for identifying GM volume alterations. Furthermore, the reproducibility of the main result was verified by a control analysis using the AAL3 atlas (Fig. 5).Discussion
We found both the DNS-D and DNS-MCI patients showed a similar GM atrophy pattern widely in the bilateral cerebral cortical, subcortical, and cerebellar regions and more severe atrophy was identified in the cerebral cortical and cerebellum rather than the deep GM nuclei in the patients with DNS-D. This suggested although widespread cortex-subcortex-cerebellum damage resulted from CO exposure, the cerebral cortex and cerebellum played a vital role in the severity of cognitive impairment.Second, we found that GM atrophy in 14 subregions of the prefrontal-occipital-temporal and bilateral cerebellar lobule VI mediate the WMH-induced cognitive impairment. Among the 14 cortical subregions, bilateral superior frontal gyrus, bilateral middle frontal gyrus, right orbital gyrus, left middle temporal gyrus, and left medioventral occipital cortex (MVOcC)_5_3 participate in regulating language, memory, execution, and emotion, whereas right fusiform gyrus, left MVOcC_5_1, left MVOcC_5_2, left lateral occipital cortex are associated with controlling perception, vision, and motion [12]. In addition, task-based and resting-state fMRI demonstrated that the bilateral cerebellar lobule VI and its adjacent regions are critical nodes in cognitive circuits [13].
We found that WMH was widely distributed in the centrum semiovale, frontal, occipital, temporal, and corpus callosum regions. As for cortical atrophy in WMH and subsequent cognitive impairment, a possible mechanism is the disruption of the large fiber bundles connecting the cerebral cortex, subcortical areas, and cerebellum, which may cause abnormal structural and functional networks connectivity, eventually leading to cognitive impairment.
Last, our GM structural analysis results differences based on a battery of methods support the notion that the results of studies using different analytical methods cannot be directly compared.
Conclusions
We found that DNS patients showed widespread GM atrophy in cortical and subcortical regions as well as the cerebellum. Patients with dementia showed more severe GM atrophies and WMH load. Our results provide preliminary evidence that the role of GM structural abnormalities in WMH-induced cognitive decline and enhance our understanding of the underlying neuromechanism of patients with DNS.Acknowledgements
The authors wish to thank the patients and their caregivers for their time and commitment to this research. The authors would also like to thank Chaoning Zhou, Zhaodong Liu, Xiaoming Chen, Dapeng Liang, Hang Guo, and Jiang Nan for their assistance in recruitment of participants and MRI scan.References
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