Evaluation of Cognitive Impairment in Patients with Minimal Hepatic Encephalopathy Based on Degree Centrality of Resting-state Blood Oxygenation Level-dependent Functional Magnetic Resonance Imaging

doi:10.12114/j.issn.1007-9572.2022.0828

Abstract

Abstract:

Background

Minimal hepatic encephalopathy has atypical clinical symptoms but mild neuropsychiatric deficits, which are easily neglected by patients and their family members as a specific type of hepatic encephalopathy. The degree centrality (DC) analysis method based on resting-state blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) is a data analysis method derived from graph-theoretic approach reflecting whole-brain network connectivity, which can provide a more complete, faster and better representation of brain function.

Objective

To explore the effects of abnormal changes in the brain functional network connectivity properties and functional brain regions on cognitive function in patients with minimal hepatic encephalopathy and their neuroimaging mechanisms.

Methods

A total of 65 patients with hepatitis B cirrhosis hospitalized in the department of infectious diseases in General Hospital of Ningxia Medical University from October 2020 to February 2022 and 40 healthy volunteers recruited during the same period were selected as the study subjects. Gender, age, education level, number connection test A (NCT-A) score, digit symbol test (DST) score and Montreal cognitive assessment (MoCA) score of the study subjects were collected. Finally, patients with hepatitis B cirrhosis were divided into cirrhosis group (n=30) and MHE group (n=28) according to NCT-A and DST scores, and the recruited healthy volunteers were considered as the healthy control group (n=34) . The DC values of brain regions in each group were calculate, the differences in DC values of brain image between MHE group and cirrhosis group, cirrhosis group and healthy control group, MHE group and healthy control group were compared, respectively. The correlations between the DC values of brain regions with the scores of NCT-A, DST and MoCA in MHE patients was analyzed by using person correlation analysis, the distribution of brain regions with DC values correlated with the scores of above scales and the corresponding scatter plots were drawn.

Results

The NCT-A score in the healthy control and cirrhotic group was lower than MHE group, DST score and MoCA score in the healthy control and cirrhotic group were higher than MHE group (P<0.05) . Compared with healthy control group, the MHE group had increased DC values in right middle frontal gyrus, left middle temporal gyrus, right inferior parietal lobule and decreased DC values in left angular gyrus, right middle occipital gyrus, right precentral gyrus (voxel cluster>18, P<0.05) . Compared with healthy control group, cirrhotic group had increased DC values in the bilateral middle temporal gyrus and decreased DC values in the left angular gyrus (voxel cluster>18, P<0.05) ; compared with cirrhotic group, MHE group had decreased values in the right middle temporal gyrus and left precuneus (voxel cluster>18, P<0.05) . The results of correlation analysis showed that in the MHE group, the DST score was correlated with DC values in the left superior temporal gyrus (r=0.639, P<0.001) , and the NCT-A score was negatively correlated with the DC values in the right inferior temporal gyrus (r=-0.722, P<0.001) ; MoCA scale score was positively correlated with DC values in the right inferior frontal gyrus and left inferior frontal gyrus (r=0.437, P=0.020; r=0.549, P=0.002) and negatively correlated with DC values in the left inferior temporal gyrus (r=-0.591, P=0.001) .

Conclusion

The abnormal functional connectivity of several brain regions and the correlation of DC values in some brain regions with NCT-A, DST and MoCA scale scores in MHE patients suggest that DC value may be a potential neuroimaging marker to quantify the severity of cognitive changes in MHE patients.

Key words: Hepatic encephalopathy, Minimal hepatic encephalopathy, Magnetic resonance imaging, Blood oxygenation level dependent functional magnetic resonance imaging, Degree centrality, Cognitive impairment, Cognition disorders

摘要：

背景

轻型肝性脑病（MHE）作为肝性脑病的一个特殊类型，临床症状不典型，且存在轻度神经、精神缺陷，易被患者及家属忽视。基于静息态血氧水平依赖功能磁共振成像（BOLD-fMRI）技术的度中心度（DC）分析方法是从图论方法衍生而来的一种反映全脑网络连接的数据分析方法，其能更完整、更快捷、更好地体现大脑功能。

目的

基于BOLD-fMRI技术的DC分析方法探究MHE患者脑功能网络连接属性的异常改变及功能脑区的异常变化对患者认知功能的影响及其神经影像机制。

方法

选取2020年10月—2022年2月在宁夏医科大学总医院感染疾病科住院的65例乙型肝炎肝硬化患者及同期招募的40例健康志愿者为研究对象，收集研究对象的性别、年龄、教育程度、数字连接实验A（NCT-A）评分、数字符号实验（DST）评分和蒙特利尔认知评估量表（MoCA）评分，根据NCT-A及DST评分最终将乙型肝炎肝硬化患者分为肝硬化组（n=30）和MHE组（n=28），招募的健康志愿者纳入健康对照组（n=34）。计算各组脑区的DC值，比较MHE组与肝硬化组、肝硬化组与健康对照组、MHE组与健康对照组脑图的DC值差异，采用Person相关分析法分析MHE患者脑区DC值与NCT-A、DST和MoCA评分的相关性，并绘制不同脑区DC值与上述量表存在相关性的脑区分布及对应散点图。

结果

健康对照组和肝硬化组的NCT-A评分低于MHE组，DST、MoCA评分高于MHE组（P<0.05）。与健康对照组相比，MHE组右侧额中回、左侧颞中回以及右侧顶下小叶DC值升高，左侧角回、右侧枕中回和右侧中央前回DC值减低（体素簇>18，P<0.05）；与健康对照组相比，肝硬化组双侧颞中回DC值升高，左侧角回DC值降低（体素簇>18，P<0.05）；与肝硬化组相比，MHE组右侧颞中回，左侧楔前叶DC值降低（体素簇>18，P<0.05）。相关性分析结果显示，MHE组DST评分与左侧颞上回的DC值呈正相关（r=0.639，P<0.001），NCT-A评分与右侧颞下回的DC值呈负相关（r=-0.722，P<0.001）；MHE组MoCA评分与右侧额下回和左侧额下回的DC值呈正相关（r=0.437，P=0.020；r=0.549，P=0.002），与左侧颞下回的DC值呈负相关（r=-0.591，P=0.001）。

结论

MHE患者多个脑区功能连接异常且部分脑区DC值与NCT-A、DST以及MoCA量表评分相关，提示DC值可能是量化MHE患者认知功能改变严重程度的潜在神经影像标志物。

关键词: 肝性脑病, 轻型肝性脑病, 磁共振成像, 静息态血氧水平依赖功能磁共振成像, 度中心度, 认知功能损害, 认知障碍

YANG Xuhong,WANG Minglei,LIU Wenxiao, et al. Evaluation of Cognitive Impairment in Patients with Minimal Hepatic Encephalopathy Based on Degree Centrality of Resting-state Blood Oxygenation Level-dependent Functional Magnetic Resonance Imaging[J]. Chinese General Practice, 2023, 26(24): 3033-3041. DOI: 10.12114/j.issn.1007-9572.2022.0828.
杨旭宏,王明磊,刘文潇等. 基于静息态血氧水平依赖功能磁共振成像技术的度中心度评价轻型肝性脑病患者认知功能损害的研究[J]. 中国全科医学, 2023, 26(24): 3033-3041. DOI: 10.12114/j.issn.1007-9572.2022.0828.

Figures/Tables 6

References 34

[1]	HANSEN M K G, KJÆRGAARD K, ERIKSEN L L，et al. Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy-current validation level and practical use[J]. Metab Brain Dis，2022,37(3):589-605. DOI：10.1007/s11011-022-00913-w.
[2]	LÓPEZ-FRANCO Ó, MORIN J P, CORTÉS-SOL A，et al. Cognitive impairment after resolution of hepatic encephalopathy：a systematic review and meta-analysis[J]. Front Neurosci，2021,15:579263. DOI：10.3389/fnins.2021.579263.
[3]	FERENCI P, LOCKWOOD A, MULLEN K，et al. Hepatic encephalopathy—definition，nomenclature，diagnosis，and quantification：final report of the working party at the 11th World Congresses of Gastroenterology，Vienna，1998[J]. Hepatology，2002,35(3):716-721. DOI：10.1053/jhep.2002.31250.
[4]	MONTAGNESE S, BAJAJ J S. Impact of hepatic encephalopathy in cirrhosis on quality-of-life issues[J]. Drugs，2019,79(1):11-16. DOI：10.1007/s40265-018-1019-y.
[5]	SORIANO G, BAJAJ J S. Grading the range of hepatic encephalopathy from overt to covert：animals to the rescue![J]. Hepatology，2017,66(1):10-12. DOI：10.1002/hep.29186.
[6]	ELSAID M I, RUSTGI V K, LOO N，et al. The burden associated with thrombocytopenia and platelet transfusions among patients with chronic liver disease[J]. J Med Econ，2020,23(4):378-385. DOI：10.1080/13696998.2019.1699563.
[7]	WU S N, ZHANG M Y, SHU H Y，et al. Changes in functional connectivity of specific cerebral regions in patients with toothache：a resting-state functional magnetic resonance imaging study[J]. Dis Markers，2020,2020:6683161. DOI：10.1155/2020/6683161.
[8]	李坤华，张清，伍建林，等. 2型糖尿病认知功能障碍患者静息态脑网络的度中心度改变[J]. 中国医学影像学杂志，2020,28(7):488-492,498. DOI：10.3969/j.issn.1005-5185.2020.07.002.
[9]	LIAO H Y, YI J Y, CAI S N，et al. Changes in degree centrality of network nodes in different frequency bands in parkinson's disease with depression and without depression[J]. Front Neurosci，2021,15:638554. DOI：10.3389/fnins.2021.638554.
[10]	BEHFAR Q, BEHFAR S K, VON REUTERN B，et al. Graph theory analysis reveals resting-state compensatory mechanisms in healthy aging and prodromal alzheimer's disease[J]. Front Aging Neurosci，2020,12:576627. DOI：10.3389/fnagi.2020.576627.
[11]	CHEN H J, JIANG L F, SUN T，et al. Resting-state functional connectivity abnormalities correlate with psychometric hepatic encephalopathy score in cirrhosis[J]. Eur J Radiol，2015,84(11):2287-2295. DOI：10.1016/j.ejrad.2015.08.005.
[12]	WANG J Y, ZHANG N P, CHI B R，et al. Prevalence of minimal hepatic encephalopathy and quality of life evaluations in hospitalized cirrhotic patients in China[J]. World J Gastroenterol，2013,19(30):4984-4991. DOI：10.3748/wjg.v19.i30.4984.
[13]	NASREDDINE Z S, PHILLIPS N A, BÉDIRIAN V，et al. The Montreal Cognitive Assessment，MoCA：a brief screening tool for mild cognitive impairment[J]. J Am Geriatr Soc，2005,53(4):695-699. DOI：10.1111/j.1532-5415.2005.53221.x.
[14]	YAN C G, WANG X D, ZUO X N，et al. DPABI：data processing&analysis for（resting-state）brain imaging[J]. Neuroinformatics，2016,14(3):339-351. DOI：10.1007/s12021-016-9299-4.
[15]	ZUO X N, EHMKE R, MENNES M，et al. Network centrality in the human functional connectome[J]. Cereb Cortex，2012,22(8):1862-1875. DOI：10.1093/cercor/bhr269.
[16]	GUO P F, HU S W, JIANG X L，et al. Associations of neurocognition and social cognition with brain structure and function in early-onset schizophrenia[J]. Front Psychiatry，2022,13:798105. DOI：10.3389/fpsyt.2022.798105.
[17]	RIZZOLATTI G, CRAIGHERO L. The mirror-neuron system[J]. Annu Rev Neurosci，2004,27:169-192. DOI：10.1146/annurev.neuro.27.070203.144230.
[18]	ZHAN C Y, CHEN H J, GAO Y Q，et al. Functional network-based statistics reveal abnormal resting-state functional connectivity in minimal hepatic encephalopathy[J]. Front Neurol，2019,10:33. DOI：10.3389/fneur.2019.00033.
[19]	GENG C F, WANG S H, LI Z L，et al. Resting-state functional network topology alterations of the occipital lobe associated with attention impairment in isolated rapid eye movement behavior disorder[J]. Front Aging Neurosci，2022,14:844483. DOI：10.3389/fnagi.2022.844483.
[20]	HAHN B, ROSS T J, STEIN E A. Neuroanatomical dissociation between bottom-up and top-down processes of visuospatial selective attention[J]. NeuroImage，2006,32(2):842-853. DOI：10.1016/j.neuroimage.2006.04.177.
[21]	LI K, ZHANG M, ZHANG H S，et al. The spontaneous activity and functional network of the occipital cortex is correlated with state anxiety in healthy adults[J]. Neurosci Lett，2020,715:134596. DOI：10.1016/j.neulet.2019.134596.
[22]	ZHANG G Y, LI Y X, ZHANG X D，et al. Identifying mild hepatic encephalopathy based on multi-layer modular algorithm and machine learning[J]. Front Neurosci，2020,14:627062. DOI：10.3389/fnins.2020.627062.
[23]	BINDER J R, DESAI R H, GRAVES W W，et al. Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies[J]. Cereb Cortex，2009,19(12):2767-2796. DOI：10.1093/cercor/bhp055.
[24]	方杰，李之豪，司丽，等. 静息态fMRI观察终末期肾病患者前扣带回皮质功能连接改变及其与认知功能的关系[J]. 中国医学影像技术，2022,38(1):32-37. DOI：10.13929/j.issn.1003-3289.2022.01.007.
[25]	WANG J J, XIE S M, GUO X，et al. Correspondent functional topography of the human left inferior parietal lobule at rest and under task revealed using resting-state fMRI and coactivation based parcellation[J]. Hum Brain Mapp，2017,38(3):1659-1675. DOI：10.1002/hbm.23488.
[26]	WANDELL B A, DUMOULIN S O, BREWER A A. Visual field maps in human cortex[J]. Neuron，2007,56(2):366-383. DOI：10.1016/j.neuron.2007.10.012.
[27]	李周乐，赵莲萍，黄刚，等. 基于静息态度中心度的T2DM共病抑郁脑功能研究[J]. 磁共振成像，2022,13(2):37-41. DOI：10.12015/issn.1674-8034.2022.02.008.
[28]	ZAFIRIS O, KIRCHEIS G, ROOD H A，et al. Neural mechanism underlying impaired visual judgement in the dysmetabolic brain：an fMRI study[J]. Neuroimage，2004,22(2):541-552. DOI：10.1016/j.neuroimage.2004.01.038.
[29]	THABUT D, KINUGAWA K, WEISS N. Diagnosis of minimal hepatic encephalopathy in patients with cirrhosis：should we bury psychometric tests?[J]. Hepatology，2014,59(6):2428. DOI：10.1002/hep.26967.
[30]	LABENZ C, TOENGES G, SCHATTENBERG J M，et al. Outcome prediction of covert hepatic encephalopathy in liver cirrhosis：comparison of four testing strategies[J]. Clin Transl Gastroenterol，2020,11(6):e00172. DOI：10.14309/ctg.0000000000000172.
[31]	YAO T, TREUE S, KRISHNA B S. Saccade-synchronized rapid attention shifts in macaque visual cortical area MT[J]. Nat Commun，2018,9(1):958. DOI：10.1038/s41467-018-03398-3.
[32]	QUIRK G J, GARCIA R, GONZÁLEZ-LIMA F. Prefrontal mechanisms in extinction of conditioned fear[J]. Biol Psychiatry，2006,60(4):337-343. DOI：10.1016/j.biopsych.2006.03.010.
[33]	杨旭宏，黄雪莹，刘文潇，等. 轻型肝性脑病患者认知功能损害的局部一致性改变：一项基于fMRI的研究[J]. 磁共振成像，2022,13(5):77-81,88. DOI：10.12015/issn.1674-8034.2022.05.014.
[34]	ZHANG G Y, CHENG Y, SHEN W，et al. Brain regional homogeneity changes in cirrhotic patients with or without hepatic encephalopathy revealed by multi-frequency bands analysis based on resting-state functional MRI[J]. Korean J Radiol，2018,19(3):452-462. DOI：10.3348/kjr.2018.19.3.452.

扫描序列	3D-T1 BRAVO	BOLD-fMRI
重复时间（ms）	7.7	2 000
回波时间（ms）	3.1	30
翻转角	12°	90°
视野（mm）	240×240	250×250
矩阵	256×256	64×64
层厚（mm）	1.2	3.6
层数	136	35
扫描时间（s）	215	360

扫描序列	3D-T1 BRAVO	BOLD-fMRI
重复时间（ms）	7.7	2 000
回波时间（ms）	3.1	30
翻转角	12°	90°
视野（mm）	240×240	250×250
矩阵	256×256	64×64
层厚（mm）	1.2	3.6
层数	136	35
扫描时间（s）	215	360

组别	例数	性别（男/女）	年龄（±s，岁）	受教育年限（±s，年）	NCT-A评分（±s，s）	DST评分（±s，分）	MoCA评分（±s，分）
健康对照组	34	24/10	44.6±7.1	7.9±1.6	36.3±8.4^b	46.3±9.6^b	26.6±1.8^b
肝硬化组	30	18/12	46.9±9.2	8.1±1.5	38.4±13.4^b	43.2±5.0^b	26.2±1.8^b
MHE组	28	19/9	47.0±9.3	7.8±1.6	70.0±14.0	21.1±5.0	20.3±3.6
F（χ²）值		0.843^a	0.801	0.952	72.473	117.516	59.567
P值		0.656	0.452	0.392	<0.001	<0.001	<0.001

组别	例数	性别（男/女）	年龄（±s，岁）	受教育年限（±s，年）	NCT-A评分（±s，s）	DST评分（±s，分）	MoCA评分（±s，分）
健康对照组	34	24/10	44.6±7.1	7.9±1.6	36.3±8.4^b	46.3±9.6^b	26.6±1.8^b
肝硬化组	30	18/12	46.9±9.2	8.1±1.5	38.4±13.4^b	43.2±5.0^b	26.2±1.8^b
MHE组	28	19/9	47.0±9.3	7.8±1.6	70.0±14.0	21.1±5.0	20.3±3.6
F（χ²）值		0.843^a	0.801	0.952	72.473	117.516	59.567
P值		0.656	0.452	0.392	<0.001	<0.001	<0.001