KL-VS基因对轻度认知障碍患者内侧颞叶体积影响的磁共振研究

doi:10.16150/j.1671-2870.2026.02.008

诊断学理论与实践 ›› 2026, Vol. 25 ›› Issue (02): 174-182.doi: 10.16150/j.1671-2870.2026.02.008

KL-VS基因对轻度认知障碍患者内侧颞叶体积影响的磁共振研究

刘小草¹^,²^,³, 曾庆泽⁴, 李依霞¹^,²^,³, 李凯程⁴, 罗骁⁴, 闫少珍¹^,²^,³, 卢洁¹^,²^,³()

¹ 首都医科大学宣武医院放射与核医学科，北京 100053
² 磁共振成像脑信息学北京市重点实验室，北京 100053
³ 神经变性病教育部重点实验室，北京 100053
⁴ 浙江大学医学院附属第二医院放射科，浙江杭州 310009

收稿日期:2025-10-27 修回日期:2026-01-04 接受日期:2026-01-05 出版日期:2026-04-25 发布日期:2026-04-25
通讯作者: 卢洁 E-mail：imaginglu@hotmail.com
基金资助:
宣武医院汇智人才项目(HZ2025PYDTR006)

The effect of KL-VS gene on medial temporal lobe volume in patients with mild cognitive impairment： A study based on MRI

LIU Xiaocao¹^,²^,³, ZENG Qingze⁴, LI Yixia¹^,²^,³, LI Kaicheng⁴, LUO Xiao⁴, YAN Shaozhen¹^,²^,³, LU Jie¹^,²^,³()

¹ Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
² Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing 100053, China
³ Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China
⁴ The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China

Received:2025-10-27 Revised:2026-01-04 Accepted:2026-01-05 Published:2026-04-25 Online:2026-04-25

摘要/Abstract

摘要：

目的：基于磁共振成像（magnetic resonance imaging，MRI），探讨Klotho基因中KL-VS功能型单倍型杂合基因（KL-VS^het）对阿尔茨海默病（Alzheimer’s disease，AD）进展中最早发生异常的脑区内侧颞叶亚区结构的影响，及其与AD病理相关认知功能下降的关系。方法：纳入AD神经影像学计划数据库中的48名受试者（2018年10月至2024年6月间，均具有全基因组关联分析数据及高分辨率磁共振数据），其中16人为KL-VS^het携带者（KL-VS^het+）[8名认知功能正常，8名存在记忆性轻度认知障碍（mild cognitive impairment，MCI）]；32名为非携带者KL-VS^het-（16名认知功能正常，16名存在MCI）。采用海马亚区自动分割软件，分析结构MRI数据，计算内侧颞叶亚区体积；利用方差分析比较组间内侧颞叶亚区体积、认知功能及病理蛋白[β-淀粉样蛋白（amyloid β-protein，Aβ）/tau蛋白]差异，并使用SPSS 27（PROCESS v4.1）软件进行交互调节效应分析。结果：KL-VS^het+者与KL-VS^het-者的内侧颞叶亚区体积、认知功能及病理蛋白（Aβ/tau蛋白）负荷存在显著差异（P<0.05）。MCI组，KL-VS^het+的左侧海马亚区阿蒙氏角（cornu Ammonis，CA）3（79.80±29.75 mm³）及齿状回（755.19±186.68 mm³）体积较KL-VS^het-（52.46±15.53 mm³、710.09±146.09 mm³）显著增大（P<0.05）；KL-VS^{het +}者的tau蛋白沉积较KL-VS^het-者显著减低（P<0.05），Aβ蛋白沉积有更低的趋势，但未发现具有统计学差异（P=0.054）。交互调节分析显示，在KL-VS^het+者中，多个内侧颞叶亚区体积对AD相关病理与认知表现之间的关联具有显著正向调节作用，且该效应主要体现在记忆评分。其中，左侧 CA3 区域体积对于 Aβ蛋白沉积与记忆功能评分之间关系、双侧多个内侧颞叶亚区体积对tau 蛋白沉积与记忆评分之间的关系表现出显著调节作用（交互项β范围为0.000 5~0.074 5，95%置信区间为-0.002 0~0.172 3，P<0.05）。结论：KL-VS^het+基因产物可能通过减缓海马等内侧颞叶区域体积萎缩，减轻MCI患者病理蛋白沉积对认知功能的损害，从而发挥神经保护作用。KL-VS^het可能作为AD治疗的新靶点。

关键词: 阿尔茨海默病, 轻度认知障碍, 磁共振成像, 内侧颞叶亚区, Klotho基因

Abstract:

Objective Based on magnetic resonance imaging (MRI), this study aims to explore the impact of the KL-VS functional haplotype heterozygous gene (KL-VS^het+) in the Klotho gene on the subregion structure of the medial temporal lobe,which presents abnormal in the brain region in the earliest progression of Alzheimer's disease (AD), as well as its relationship with the decline in cognitive function associated with AD pathology. Methods A total of 48 participants from the AD Neuroimaging Initiative database (with genome-wide association analysis data and high-resolution magnetic resonance ima-ging data from October 2018 to June 2024) were enrolled, comprising 16 KL-VS^het+ carriers [8 cognitively normal, CN; 8 amnestic mild cognitive impairment (MCI), aMCI] and 32 non-carriers (KL-VS^het-) (16 CN and 16 aMCI). Structural MRI data were analyzed using automatic segmentation of hippocampal subfields to calculate medial temporal lobe subregion volumes. Group differences in medial temporal lobe subregion volume, cognitive function, and pathological proteins (amyloid β- protein, Aβ/tau protein) were compared using analysis of variance. Moderation analysis was conducted with SPSS 27 (PROCESS v4.1). Results Significant differences were observed between KL-VS^het+ and KL-VS^het- individuals in medial temporal lobe subregion volumes, cognitive function, and pathological protein (Aβ/tau) burden (P<0.05). In the MCI group, KL-VS^het+ carriers showed significantly larger volumes in the left hippocampal subfield cornu ammonis 3 (CA3) (79.80±29.75 mm³) and dentate gyrus (755.19±186.68 mm³) compared to KL-VS^het- individuals (52.46±15.53 mm³, 710.09±146.09 mm³) (P<0.05). Tau protein deposition was significantly lower in KL-VS^het+ individuals than in KL-VS^het- individuals (P<0.05), and Aβ deposition showed a lower trend, although the difference did not reach statistical significance (P=0.054). Moderation analysis showed that, among KL-VS^het+ individuals, the volumes of multiple medial temporal lobe subregions had significant positive moderating effects on the relationship between AD-related pathology and cognitive performance, mainly reflected in memory scores. The volume of the left CA3 subregion significantly moderated the relationship between Aβ deposition and memory function scores, while the volumes of multiple bilateral medial temporal lobe subregions significantly moderated the relationship between tau deposition and memory scores (interaction term β ranged from 0.000 5 to 0.074 5, and the 95% confidence interval ranged from -0.002 0 to 0.172 3, P<0.05). Conclusions The KL-VS^het+ gene product may exert a neuroprotective effect by slowing down the volume atrophy of medial temporal lobe regions, such as the hippocampus, thereby mitigating the damage to cognitive function caused by pathological protein deposition in patients with mild cognitive impairment (MCI). KL-VS^het may serve as a novel therapeutic target for Alzheimer's disease (AD).

Key words: Alzheimer's disease, Mild cognitive impairment, Magnetic resonance imaging, Medial temporal lobe subregions, Klotho gene

中图分类号:

R741
R445

刘小草, 曾庆泽, 李依霞, 李凯程, 罗骁, 闫少珍, 卢洁. KL-VS基因对轻度认知障碍患者内侧颞叶体积影响的磁共振研究[J]. 诊断学理论与实践, 2026, 25(02): 174-182.

LIU Xiaocao, ZENG Qingze, LI Yixia, LI Kaicheng, LUO Xiao, YAN Shaozhen, LU Jie. The effect of KL-VS gene on medial temporal lobe volume in patients with mild cognitive impairment： A study based on MRI[J]. Journal of Diagnostics Concepts & Practice, 2026, 25(02): 174-182.

图/表 7

图1

表1

表2

图2

图3

图4

表3

交互调节效应

Subre- gions	Independent variable	Dependent variable	β（subregions× pathology× KL-VS）	SE	t	P	LLCI	ULCI	∆R2	KL-VS^het-		KL-VS^het+
Subre- gions	Independent variable	Dependent variable	β（subregions× pathology× KL-VS）	SE	t	P	LLCI	ULCI	∆R2	β	P	β	P
L_CA3	Aβ-CL	MEM	0.0005	0.000 2	2.710 0	0.010 3	0.000 1	0.000 8	0.112 9	-0.000 1	0.702 3	0.000 4	0.001 0
L_CA3	Aβ-CL	MoCA	0.002 5	0.001 2	2.033 1	0.049 7	0.000 0	0.005 0	0.076 0	-0.001 0	0.272 1	0.001 5	0.082 0
L_DG	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.028 1	0.009 5	2.974 6	0.005 5	0.008 9	0.047 4	0.120 4	-0.004 9	0.179 7	0.023 3	0.012 3
L_ERC	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.026 5	0.012 4	2.142 7	0.039 8	0.001 3	0.051 7	0.056 1	-0.004 5	0.276 3	0.022 0	0.068 8
L_PHC	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.034 1	0.017 7	1.923 5	0.063 3	-0.002 0	0.070 2	0.062 5	-0.000 8	0.080 4	0.033 3	0.065 4
R_CA1	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.019 1	0.008 4	2.260 5	0.030 7	0.001 9	0.036 3	0.082 9	-0.003 3	0.168 6	0.015 8	0.060 6
R_DG	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.038 5	0.014 9	2.587 5	0.014 4	0.008 2	0.068 8	0.099 9	-0.005 6	0.039 6	0.032 9	0.031 9
R_SUB	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.087 3	0.041 7	2.091 4	0.044 5	0.002 3	0.172 3	0.073 9	-0.003 9	0.606 0	0.083 4	0.050 7
R_BA35	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.038 1	0.014 3	2.670 4	0.011 8	0.009 0	0.067 2	0.110 4	-0.012 0	0.084 3	0.026 1	0.046 2
L_DG	tau meta temporal SUVR	MEM	0.018 8	0.007 7	2.435 0	0.020 6	0.003 1	0.034 5	0.083 3	-0.003 1	0.275 5	0.015 7	0.036 6
R_DG	tau meta temporal SUVR	MEM	0.026 4	0.012 5	2.123 2	0.041 6	0.001 1	0.051 8	0.070 0	-0.004 0	0.067 3	0.022 5	0.076 5
R_BA35	tau meta temporal SUVR	MEM	0.031 2	0.126 0	2.471 2	0.019 0	0.005 5	0.056 8	0.095 1	-0.007 5	0.169 0	0.023 7	0.046 5
L_CA1	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.016 3	0.006 7	2.440 9	0.020 4	0.002 7	0.029 9	0.077 6	-0.004 4	0.206 7	0.011 9	0.046 3
L_DG	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.028 1	0.007 9	3.535 9	0.001 3	0.011 9	0.044 2	0.160 5	-0.007 7	0.072 7	0.020 4	0.005 1
L_Sub	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.052 7	0.023 0	2.295 6	0.028 4	0.005 9	0.099 5	0.076 4	-0.009 8	0.408 5	0.042 9	0.037 3
L_ERC	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.034 1	0.011 0	3.095 2	0.004 1	0.011 6	0.056 5	0.109 0	-0.010 0	0.134 2	0.024 0	0.010 6
L_PHC	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.035 2	0.016 3	2.152 6	0.039 0	0.001 9	0.068 4	0.079 7	-0.002 9	0.537 6	0.032 2	0.047 6
R_CA1	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.016 8	0.006 9	2.432 6	0.020 8	0.002 7	0.030 8	0.093 1	-0.002 6	0.315 0	0.014 2	0.034 2
R_DG	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.032 9	0.010 5	3.115 2	0.003 9	0.011 4	0.054 3	0.138 6	-0.005 0	0.089 9	0.027 9	0.009 9
R_SUB	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.074 5	0.029 1	2.558 8	0.015 4	0.015 2	0.133 9	0.105 4	-0.008 3	0.353 2	0.066 2	0.023 2
R_ERC	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.0280	0.012 2	2.287 0	0.029 0	0.003 1	0.052 8	0.084 7	-0.006 9	0.306 6	0.021 0	0.048 4
R_BA35	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.039 3	0.012 1	3.257 5	0.002 7	0.014 7	0.063 9	0.148 7	-0.009 8	0.178 3	0.029 5	0.004 8
R_BA36	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.010 9	0.004 5	2.430 5	0.020 9	0.001 8	0.020 0	0.100 4	-0.002 2	0.348 7	0.008 7	0.030 8
R_HIPP	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.009 5	0.004 2	2.285 3	0.028 9	0.001 0	0.018 0	0.079 1	-0.001 8	0.193 9	0.007 7	0.058 9

表3

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Item	KL-VS^het-CN	KL-VS^het-MCI	KL-VS^het+CN	KL-VS^het+MCI	F（χ²）	P
Number	16	16	8	8	/	/
Age(years)	76.36±3.99	74.44±7.49	76.05±5.17	78.36±6.40	0.775	0.514
Female [N (%)]	2(12.5)	9(56.25)	4(50)	1(12.5)	/	0.024
APOE ε4 carrier [N (%)]	6(60)	8(50)	4(50)	3(37.5)	/	0.536
Education(years)	17.88±2.09	16.94±2.32	17.63±2.13	17.29±2.20	0.913	0.443
MMSE (total)	28.94±1.12	26.25±4.48	29.63±1.06	27.13±2.23	3.611	0.02^a,d
MoCA (total)	25.19±2.81	21.94±3.80	24.63±2.88	22.88±2.99	3.123	0.035^a
Memory function (z-score)	0.49±0.33	0.03±0.56	0.73±0.57	0.29±0.35	5.035	0.001^a,c,d,f
Executive function (z-score)	0.70±0.37	0.34±0.75	0.75±0.45	0.45±0.55	1.554	0.214
Language function (z-score)	0.45±0.33	0.34±0.65	0.76±0.41	0.20±0.48	1.956	0.135^f
Aβ PET centiloid unit	27.85±28.43(16)	70.90±54.53(15)	42.59±44.49(7)	41.05±66.23(7)	2.200	0.103^a
tau Braak Ⅰ-Ⅱ SUVR(N)	1.18±0.21(14)	1.45±0.27(15)	1.13±0.08(6)	1.15±0.13(7)	5.946	0.002^a,d,e
tau Braak Ⅲ-Ⅳ SUVR(N)	1.17±0.17(14)	1.31±0.27(15)	1.13±0.03(6)	1.12±0.16(6)	2.096	0.117
tau Braak Ⅴ-Ⅵ SUVR(N)	1.05±0.10(14)	1.17±0.20(15)	1.05±0.06(6)	1.01±0.15(6)	2.63	0.64^a,e
tau META TEMporal SUVR(N)	1.22±0.24(14)	1.42±0.35(15)	1.18±0.02(6)	1.19±0.18(6)	2.106	0.116

Item	KL-VS^het-CN	KL-VS^het-MCI	KL-VS^het+CN	KL-VS^het+MCI	F（χ²）	P
L_CA1	1287.70±114.45	1191.64±211.91	1324.33±200.95	1118.70±208.09	2.303	0.091^c,f
L_CA2	1.57±1.26	1.11±0.61	1.53±1.21	0.74±0.46	1.275	0.300
L_CA3	56.37±16.37	52.46±15.53	56.88±20.81	72.80±29.75	1.799	0.162^e
L_DG	782.93±68.93	710.09±146.09	797.66±98.31	755.19±186.68	1.234	0.309^c,e
L_SUB	447.20±83.46	403.47±52.35	447.50±87.31	382.98±69.07	1.959	0.135
L_ERC	456.30±66.04	369.30±79.03	398.13±101.39	387.99±128.81	2.671	0.060
L_BA35	531.47±89.16	472.24±92.27	496.34±117.24	452.86±90.28	1.475	0.235
L_BA36	1824.36±305.82	1605.57±266.88	1655.54±295.64	1599.68±448.21	1.502	0.228
L_PHC	757.33±165.20	722.16±164.32	713.10±140.74	693.08±143.82	0.317	0.813
L_CA	1346.21±123.47	1245.00±220.02	1382.17±192.91	1148.32±244.44	2.717	0.056^c,f
L_HIPP	2129.15±150.98	1955.09±358.11	2179.83±261.27	1859.12±441.02	2.283	0.093^f
R_CA1	1173.77±119.59	1158.21±230.51	1266.84±162.16	1118.00±267.69	0.823	0.489
R_CA2	7.84±3.27	8.19±4.12	9.38±2.72	6.68±1.04	0.778	0.513
R_CA3	62.04±27.89	56.02±16.18	65.20±26.54	72.71±38.17	0.716	0.548
R_DG	792.12±99.14	788.20±165.25	852.15±73.66	751.24±140.99	0.803	0.499
R_SUB	443.26±85.09	434.48±75.11	477.25±80.70	387.62±48.23	1.750	0.171^f
R_ERC	491.23±102.61	415.65±98.74	433.40±101.50	464.73±167.08	1.262	0.300
R_BA35	512.29±101.25	487.86±87.79	483.05±65.29	437.77±152.33	0.873	0.463
R_BA36	1805.15±450.28	1574.03±250.67	1752.69±267.92	1591.25±510.68	1.225	0.313
R_PHC	774.14±126.18	787.02±125.03	759.42±110.75	764.08±283.94	0.069	0.976
R_CA	1243.64±136.95	1222.42±242.02	1341.42±154.19	1157.59±296.30	1.065	0.378
R_HIPP	2035.76±204.99	2010.62±400.06	2193.57±213.55	1882.69±430.93	1.225	0.312

KL-VS基因对轻度认知障碍患者内侧颞叶体积影响的磁共振研究

The effect of KL-VS gene on medial temporal lobe volume in patients with mild cognitive impairment： A study based on MRI

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