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. 2022 Mar 4:16:807585.
doi: 10.3389/fnins.2022.807585. eCollection 2022.

Abnormal Cerebrovascular Reactivity and Functional Connectivity Caused by White Matter Hyperintensity Contribute to Cognitive Decline

Dan Yang  1 , Ruomeng Qin  1 , Lan Chu  2 , Hengheng Xu  1 , Ling Ni  1 , Junyi Ma  1 , Pengfei Shao  1 , Lili Huang  1 , Bing Zhang  3 , Meijuan Zhang  1   4   5   6 , Yun Xu  1   4   5   6
Affiliations

Abnormal Cerebrovascular Reactivity and Functional Connectivity Caused by White Matter Hyperintensity Contribute to Cognitive Decline

Dan Yang et al. Front Neurosci. .

Abstract

Aims: This study aimed to investigate the relationships of impaired cerebrovascular reactivity (CVR) and abnormal functional connectivity (FC) with white matter hyperintensity (WMH)-related cognitive decline.

Methods: A total of 233 WMH subjects were recruited and categorized into WMH-I (n = 106), WMH-II (n = 72), and WMH-III (n = 55) groups according to Fazekas visual rating scale. All participants underwent neuropsychological tests and multimodal MRI scans, including 3D-T1, and resting-state functional magnetic resonance imaging (rs-fMRI). The alterations of CVR maps and FC were further explored.

Results: Subjects with a higher WMH burden displayed a lower CVR in the left medial occipital gyrus (MOG). The FC analysis using MOG as a seed revealed that the FC of the left insula, left inferior parietal lobule, and thalamus changed abnormally as WMH aggravated. After adjusting for age, gender, and education years, the serial mediation analysis revealed that periventricular white matter hyperintensity contributes indirectly to poorer Mini-Mental State Examination (MMSE) scores (indirect effect: β = -0.1248, 95% CI: -0.4689, -0188), poorer Montreal Cognitive Assessment (MoCA) (indirect effect: β = -0.1436, 95% CI: -0.4584, -0.0292) scores, and longer trail making tests A (TMT-A) (indirect effect: β = 0.1837, 95% CI: 0.0069, 0.8273) times, specifically due to the lower CVR of the left MOG and the higher FC of the left insula-MOG.

Conclusion: The CVR decline of the left MOG and the abnormal FC of the left insula-MOG attributed to WMH progression were responsible for the poor general cognition (MMSE and MoCA) and information processing speed (TMT-A). The left MOG may act as a connection, which is involved in the processing of cognitive biases by connecting with the left insula-cortical regions in WMH individuals.

Keywords: cerebrovascular reactivity; cognitive decline; functional connectivity; rs-fMRI; white matter hyperintensity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Group differences of CVR across the three groups. (A) Axial CVR mapping for each WMH cohort. (B) The brain areas displayed a significant difference among the three groups (left MOG). (C) The subjects in the WMH-II and WMH-III groups displayed a significantly lower CVR in the left MOG than the subjects in the WMH-I group. CVR, cerebrovascular reactivity; MOG, middle occipital gyrus; WMH, white matter hyperintensity.
FIGURE 2
FIGURE 2
Group differences of FC across the three groups. (A) The regions displayed a significant difference among the three groups (left insula, left IPL, and thalamus). FC, functional connectivity; IPL, inferior parietal lobule. (B) The subjects in WMH-III displayed a significantly greater FC in the left IPL than the subjects in the other two groups. (C) The subjects in the WMH-III group displayed a significantly higher FC in the left insula than the subjects in the other two groups. (D) The subjects in the WMH-III and WMH-II groups displayed a significantly greater FC in the thalamus than the subjects in the WMH-I group. FC, functional connectivity; IPL, inferior parietal lobule; WMH, white matter hyperintensity.
FIGURE 3
FIGURE 3
Correlation analyses between cognitive function and CVR of the left MOG in the white matter hyperintensity (WMH)-III group. (A) The CVR of the left MOG was positively correlated with MoCA score (r = 0.291, P = 0.036). (B) The CVR of the left MOG was negatively correlated with the time of SCWT-A (r = –0.331, P = 0.016). (C) The CVR of the left MOG was negatively correlated with the time of SCWT-C (r = –0.382, P = 0.005). (D) The CVR of the left MOG was negatively correlated with the time of TMT-A (r = –0.318, P = 0.021). The scores were z-transformed scores of the relevant tests. CVR, cerebrovascular reactivity; MOG, middle occipital gyrus; MoCA, Montreal Cognitive Assessment; SCWT, Stroop Color and Word Tests; TMT, Trail Making Test.
FIGURE 4
FIGURE 4
Correlation analyses between FCs and cognitive function in the white matter hyperintensity (WMH)-III group. (A) The FC of the left insula-MOG was positively correlated with MMSE score (r = 0.356, P = 0.010). (B) The FC of the left insula-MOG was positively correlated with the MoCA score (r = –0.401, P = 0.003). (C) The FC of the left insula-MOG was negatively correlated with the time of SCWT-A (r = –0.308, P = 0.026). (D) The FC of the left insula-MOG was negatively correlated with the time of TMT-A (r = –0.497, P < 0.001). (E) The FC of the left IPL-MOG was negatively correlated with the time of TMT-A (r = –0.328, P = 0.018). The scores were z-transformed scores of the relevant tests. FC, functional connectivity; IPL, inferior parietal lobule; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; SCWT, Stroop Color and Word Tests; TMT, Trail Making Test.
FIGURE 5
FIGURE 5
Path models show the direct and indirect relationships between white matter hyperintensity volume and cognitive function. The significant pathways are highlighted in red lines. For each connection, the standard coefficient and P-value are shown. The direct and indirect effect and their 95% CI are also shown. (A) TWMH volume was indirectly associated with poorer MMSE score through aberrant CVR of left MOG and FC of left insula-MOG (Indirect effect: −0.1499, 95% CI [−0.6165, −0.0213]. (B) TWMH volume was indirectly associated with poorer MoCA score through aberrant CVR of left MOG and FC of left insula-MOG (Indirect effect: −0.1714, 95% CI [−0.5833, −0.0300]. (C) TWMH volume was indirectly associated with longer TMT-A time through aberrant CVR of left MOG and FC of left insula-MOG (Indirect effect: −0.2218, 95% CI [0.0056, 1.0234]. (D) PWMH volume was indirectly associated with poorer MMSE score through aberrant CVR of left MOG and FC of left insula-MOG (Indirect effect: −0.1248, 95% CI [−0.4689, −0.0188]. (E) PWMH volume was indirectly associated with poorer MoCA score through aberrant CVR of left MOG and FC of left insula-MOG (Indirect effect: −0.1436, 95% CI [−0.4584, −0.0292]. (F) PWMH volume was indirectly associated with longer TMT-A time through aberrant CVR of left MOG and FC of left insula-MOG (Indirect effect: 0.1837, 95% CI [0.0069, 0.8273]. CI, confidence interval; CVR, cerebrovascular reactivity; FC, functional connectivity; MOG, middle occipital gyrus; TWMH, total white matter hyperintensity; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; TMT, Trail Making Test; PWMH, periventricular white matter hyperintensity.
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