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临床研究
高原藏族2型糖尿病患者静息态磁共振成像研究:基于低频振幅和比率低频振幅
何万林 李谨利 冯莉 胡鑫 郭勇跃 何媛媛 李恒演 朱中原 孟金丽

Cite this article as: HE W L, LI J L, FENG L, et al. Study on resting-state functional magnetic resonance imaging in plateau Tibetan with type 2 diabetes mellitus: Amplitude of low-frequency fluctuations and fractional amplitude of low-frequency fluctuations[J]. Chin J Magn Reson Imaging, 2023, 14(5): 72-78, 122.本文引用格式:何万林, 李谨利, 冯莉, 等. 高原藏族2型糖尿病患者静息态磁共振成像研究:基于低频振幅和比率低频振幅[J]. 磁共振成像, 2023, 14(5): 72-78, 122. DOI:10.12015/issn.1674-8034.2023.05.014.


[摘要] 目的 旨在探索久居高原环境的藏族2型糖尿病患者(plateau Tibetan type 2 diabetes mellitus, PTDM)与高原藏族健康对照(plateau Tibetan healthy control, PTHC)静息态功能磁共振成像(resting-state functional magnetic resonance imaging, rs-fMRI)局部功能指标的差异及其与认知功能的关系。材料与方法 本研究纳入53名PTDM患者和51名年龄、性别、教育程度匹配良好的PTHC。收集两组患者的人口学资料、临床检验检查结果、神经心理学测试结果和rs-fMRI数据,将rs-fMRI功能指标低频振幅(amplitude of low-frequency fluctuations, ALFF)、比率低频振幅(fractional amplitude of low-frequency fluctuations, fALFF)进行基于体素间的组间差异比较,探究PTDM和PTHC两组间ALFF、fALFF值的差异脑区,及其与人口学、临床检验检查指标和神经心理学测试结果的相关性。结果 与PTHC组相比,PTDM组ALFF值在双侧小脑Ⅷ区降低(P<0.05,FWE校正),fALFF值在右侧舌回、左侧小脑Ⅰ区降低(P<0.05,FWE校正)。相关分析显示,PTDM组患者左侧小脑Ⅷ区(r=0.376,P=0.006)、右侧小脑Ⅷ区(39,-54,-54)(r=0.411,P=0.002)、右侧小脑Ⅷ区(15,-66,-54)(r=0.377,P=0.005)、右侧舌回fALFF值(r=0.337,P=0.014)与年龄呈正相关;PTDM组患者左侧小脑Ⅷ区ALFF值与低密度胆固醇(r=-0.283,P=0.049)、糖化血红蛋白(r=-0.320,P=0.028)、两小时血糖(r=-0.405,P=0.016)呈负相关;右侧舌回fALFF值与Zung氏焦虑自评量表呈负相关(r=-0.399,P=0.012),左侧小脑Ⅰ区fALFF值与吸烟时间呈正相关(r=0.407,P=0.006),与匹兹堡睡眠质量指数量表(r=-0.327,P=0.033)、抑郁自评量表(r=-0.320,P=0.041)及患者健康问卷得分(r=-0.339,P=0.035)呈负相关。结论 高原藏族T2DM患者rs-fMRI局部功能指标在小脑和右侧舌回减低,并与年龄、血糖指标、神经心理及认知功能相关。探究高原藏族T2DM患者的脑功能变化可以更好地了解与疾病相关的认知功能变化及相关机制。
[Abstract] Objective To explore the differences in regional activity of resting-state functional magnetic resonance imaging (rs-fMRI) between plateau Tibetan with type 2 diabetes mellitus (T2DM) living in a plateau environment and healthy plateau Tibetan, and their relationship with cognitive function.Materials and Methods Fifty-three plateau Tibetan with type 2 diabetes mellitus (PTDM) and 51 plateau Tibetan healthy control (PTHC) in the analysis after age and sex matched were included in this study. Demographic, clinical data, neuropsychological test and rs-fMRI data were collected of both groups, and the rs-fMRI functional indexes the amplitude of amplitude of low-frequency fluctuations (ALFF) and fractional amplitude of low-frequency fluctuation (fALFF) were compared between two groups based on voxels to investigate the differences. We investigated the differences in ALFF and fALFF values between PTDM and PTHC groups and their correlation with demographics, clinical data and neuropsychological test results.Results Compared with the PTHC group, the PTDM group had reduced ALFF values in bilateral cerebellar region Ⅷ ) and reduced fALFF values in the right lingual gyrus and left cerebellar region I (P<0.05, FWE correction). Correlation analysis showed that the fALFF values of left cerebellar area Ⅷ (r=0.376, P=0.006), right cerebellar area Ⅷ (39, -54, -54) (r=0.411, P=0.002), right cerebellar area Ⅷ (15, -66, -54) (r=0.377, P=0.005) and right lingual gyrus (r=0.337, P=0.014) in the PTDM group were positively correlated with age; in the PTDM group were negatively correlated with low-density cholesterol (r=-0.283, P=0.049), glycated hemoglobin (r=-0.320, P=0.028) and two-hour glucose (r=-0.405, P=0.016). fALFF values of right lingual gyrus in the PTDM group were negatively correlated with Zung's anxiety self-rating scale (r=-0.399, P=0.012); fALFF values of left cerebellar area I in the PTDM group were positively correlated with smoking time (r=0.407, P=0.006), and negatively correlated with Pittsburgh Sleep Quality Index Scale (r=-0.327, P=0.033), Depression Self-Rating Scale (r=-0.320, P=0.041) and patient health questionnaire scores (r=-0.339, P=0.035).Conclusions The rs-fMRI regional activity is reduced in the cerebellum and right lingual gyrus in plateau Tibetan with type 2 diabetes mellitus compared to healthy controls, and correlated with age, glucose indicators, neuropsychology and cognitive function. Exploring the changes in brain function in Tibetan with type 2 diabetes mellitus can provide a better understanding of disease-related changes in cognitive function and related mechanisms.
[关键词] 2型糖尿病;高原藏族;低频振幅;比率低频振幅;功能磁共振成像
[Keywords] type 2 diabetes mellitus;plateau Tibetan;amplitude of low-frequency fluctuations;fractional amplitude of low-frequency fluctuations;resting-state magnetic resonance imaging

何万林 1   李谨利 2   冯莉 1   胡鑫 1   郭勇跃 1   何媛媛 1   李恒演 1   朱中原 1   孟金丽 1, 3*  

1 西藏自治区人民政府驻成都办事处医院放射科,成都 610041

2 简阳市人民医院放射科,成都 641499

3 四川大学华西磁共振研究中心,成都 610041

通信作者:孟金丽,E-mail:372042100@qq.com

作者贡献声明:孟金丽设计本研究的方案,对稿件的重要内容进行了修改;何万林起草和撰写稿件,获取、分析或解释本研究的数据;李谨利、冯莉、胡鑫、郭勇跃、何媛媛、李恒演、朱中原获取、分析或解释本研究的数据,对稿件的重要内容进行了修改;孟金丽获得了四川省科技计划资助项目、四川省医学科研课题、西藏自治区科学技术厅中央引导地方科学发展资金、西藏自治区人民政府驻成都办事处医院院级重点项目的资助。全体作者都同意发表最后的修改稿,同意对本研究的所有方面负责,确保本研究的准确性和诚信。


基金项目: 四川省科技计划资助项目 2021YJ0161 四川省医学科研课题 Q20042 西藏自治区科学技术厅中央引导地方科学发展资金 XZ202102YD0032C 西藏自治区人民政府驻成都办事处医院院级重点项目 2021-YJ-2
收稿日期:2022-12-08
接受日期:2023-05-06
中图分类号:R445.2  R587.1 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2023.05.014
本文引用格式:何万林, 李谨利, 冯莉, 等. 高原藏族2型糖尿病患者静息态磁共振成像研究:基于低频振幅和比率低频振幅[J]. 磁共振成像, 2023, 14(5): 72-78, 122. DOI:10.12015/issn.1674-8034.2023.05.014.

0 前言

       糖尿病是一种以长期高血糖水平及胰岛素抵抗为特点的代谢性疾病,与痴呆、认知功能减退和情绪障碍相关[1]。在一项大样本中国糖尿病患病率和民族分布情况的调查中,藏族人口的糖尿病发病率为4.3%,且高原藏族人群糖尿病知晓率、治疗率和控制率都低于全国平均水平[2]。糖尿病具有血糖水平高、血糖控制差、并发症多等特点[3],其导致的认知功能障碍与糖尿病发病年龄、疾病持续时间、慢性高血糖和高胰岛素血症等风险因素相关[4]。2型糖尿病(type 2 diabetes mellitus, T2DM)患者的认知功能下降、焦虑抑郁情绪与大脑的结构和功能改变相关[5]

       既往基于静息态功能磁共振成像(resting-state functional magnetic resonance imaging, rs-fMRI)针对平原糖尿病患者认知功能障碍机制的分析发现,以内侧前额叶皮层、视觉皮层和颞上回活动减退为特征的区域性自发神经活动改变可能是T2DM的潜在神经病理机制[5];另一项研究则认为全脑静息状态大脑活动明显降低,包括双侧舌回、左中央后回、右颞下回、右小脑顶、右岛叶和右后扣带皮层[6]。这些研究表明,rs-fMRI能够反映T2DM患者的脑功能变化,揭示T2DM这类慢性疾病对脑功能的影响。然而,藏族人群在遗传背景、文化、生活方式、饮食模式及久居低压缺氧环境方面与汉族存在很大差异。这些因素通过自然选择的基因突变及表达,对高原藏族人群大脑的结构和功能产生影响[7]。一项关于高原藏族人群基于体素的形态学测量及低频振幅(amplitude of low-frequency fluctuation, ALFF)变化的研究表明,相较于平原健康人,高原藏族健康人双侧中央后回及右舌回的灰质体积减小,右楔前叶ALFF减少,表明高原藏族人群与平原人群脑结构和功能存在差异[8]。然而,相较于平原人群糖尿病的脑功能研究,目前尚无关于高原藏族人群糖尿病的脑功能研究,无针对高原藏族2型糖尿病患者(plateau Tibetan type 2 diabetes mellitus, PTDM)和高原藏族健康对照(plateau Tibetan Health control, PTHC)的rs-fMRI局部功能指标差异的研究,T2DM对高原藏族人群脑功能的影响尚不明确。

       人脑能够产生大量振荡波支持大脑功能,ALFF和比率低频振幅(fractional amplitude of low-frequency fluctuation, fALFF)被用于测量这样的自发低频振荡的振幅[9],在一定程度上标志着神经元活动的强弱。ALFF更容易受到生理源性噪声的影响,特别是在心室和大血管附近,fALFF对这类非特异性的信号成分具有抑制作用,但在重复检测可靠性方面,ALFF往往高于fALFF[9]。因此,ZUO等[9]推荐同时报告两种指标的结果,以弥补各自的局限性。本研究旨在了解PTDM和PTHC各脑区间rs-fMRI局部功能指标ALFF和fALFF的差异,分析差异脑区与人口统计学、临床检验检查指标和神经心理学测试结果的相关性,探讨PTDM患者差异脑区局部功能指标改变与其关系,探索PTDM人群脑认知功能改变,有助于早期发现PTDM患者隐匿性的脑功能损伤,提示患者认知功能及焦虑抑郁情绪的发生风险。

1 材料与方法

1.1 一般资料

       前瞻性纳入2020年4月至2021年10月于西藏自治区人民政府驻成都办事处医院就诊的PTDM患者53例,同时招募与PTDM患者年龄、性别和教育程度相匹配的PTHC 51例,年龄为20~75岁。本研究遵守《赫尔辛基宣言》,得到西藏自治区人民政府驻成都办事处医院伦理学委员会批准[批准文号:(2020)年科研第30号]。全体受试者均在检查前对本研究知情同意,并签署了知情同意书。

       PTDM组纳入标准:(1)长期生活在高原的藏族人。(2)根据2014年美国糖尿病协会最新的标准诊断为T2DM患者。a.糖化血红蛋白>6.5%(48 mmol/mol);b.空腹血糖≥7.0 mmol/L(126 mg/dL);c.口服葡萄糖耐量试验餐后两小时血糖11.1 mmol/L(200 mg/dL);d.高血糖或高血糖症状和随机血糖>11.1 mmol/L(200 mg/dL),无高血糖症状。符合上述四项中1~3项即可诊断为T2DM。(3)无严重的糖尿病并发症。(4)右利手。(5)接受过糖尿病药物或非药物治疗(饮食控制等)。(6)受试者纳入研究时返回平原居住时间小于三个月。排除标准:(1)已知的脑外伤史、癫痫、中风、酒精和其他物质依赖、帕金森氏病、严重抑郁症或其他可能影响认知功能的疾病(如癌症);(2)MRI禁忌证;(3)住院期间出现低血糖(血糖<3.9 mmol/L)或高血糖(血糖>33.3 mmol/L)的患者。PTHC组纳入标准:(1)高原藏族;(2)右利手;(3)上述T2DM诊断的所有标准均不满足者;(4)受试者纳入研究时返回平原居住时间小于三个月。排除标准与PTDM组的(1)(2)一致。

1.2 临床资料采集

       通过病历和问卷调查收集患者病史及临床数据,包括年龄、性别、民族、居住海拔、身体质量指数(body mass index, BMI)、受教育年限、既往史、吸烟/饮酒史。每天测量三次坐位血压并取平均值。血常规检查包括血红蛋白、红细胞、红细胞压积、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、极低密度脂蛋白胆固醇。血糖检测包括葡萄糖、糖化血清蛋白、糖化血红蛋白(glycosylated hemoglobin, HbA1c)、空腹血糖、两小时血糖、空腹胰岛素、两小时胰岛素等实验室资料,所有检查均在禁食8 h后进行。

1.3 神经心理学测试

       神经心理学测试用于评估参与者的一般心理状态和认知功能,所有参与者都接受了一系列神经心理学测试,这些测试评估了生活质量、焦虑、抑郁、一般认知功能、数字处理速度、逻辑记忆和视觉空间记忆等。所有受试者在接受rs-fMRI扫描前,需完成以下量表测试:

       (1)生活质量:匹兹堡睡眠质量指数(Pittsburgh Sleep Quality Index, PSQI)[10]、患者健康问卷-9(Patient Health Status Questionnaire-9, PHQ-9)[11]和健康自评量表(Generalized Anxiety Disorder, GAD-7)[12]。(2)焦虑和抑郁症状:抑郁自评量表(Self-rating Depression Scale, SDS)[13]和Zung's焦虑自评量表(Zung's Self Rating Anxiety Scale, SAS)[14];(3)一般认知功能:蒙特利尔神经心理学测试得分量表北京版(Montreal Cognitive Assessment, MoCA)[15]和简易智力状态检查量表(Mini-Mental State Examination, MMSE)[16];(4)数字处理速度[17]:数字广度测试-顺背(Digit Span Test-straight back, DST-straight back)和数字广度测试-倒背(Digit Span Test-recite backwards, DST-recite backwards);(5)逻辑记忆[18]:逻辑记忆Ⅰ(即刻)和逻辑记忆Ⅱ(延迟);(6)视觉空间记忆[19]:视觉空间记忆Ⅰ(即刻)和视觉空间记忆Ⅱ(延迟)。

1.4 影像数据采集

       采用飞利浦 Achieva TX 3.0 T MR扫描仪和8通道颅脑相控阵列表面线圈进行MRI扫描,所有受试者均使用相同参数进行常规序列和rs-fMRI扫描。执行常规序列筛查以排除颅内病变。在扫描的过程中,使受试者保持平卧、闭眼,采用海绵垫固定头部减少头动,采用耳塞减少噪音,并嘱受试者保持清醒。所有操作由同一名放射科技师完成。扫描参数:(1)rs-fMRI采用基于梯度回波的平面回波序列,TR 2000 ms,TE 30 ms,FOV 220 mm×220 mm,矩阵64×64,翻转角90°,采集240个时间点,层厚3.7 mm,层间距0 mm,无间隔连续扫描38层。(2)三维T1加权成像采用扰相梯度回波序列行轴位扫描,TR 8.1 ms,TE=3.7 ms,FOV 256 mm×256 mm,矩阵256×203,翻转角12°,层厚1 mm,层间距0 mm,无间隔连续扫描188层。

1.5 数据预处理

       采用Matlab软件(R2018b,https://www.mathworks.com/products/matlab.html)和工具包SPM(12,https://www.fil.ion.ucl.ac.uk/spm/)及Dpabi(Advance V3.1,http://rfmri.org/comment/6239)对rs-fMRI数据进行预处理。该处理过程包括去除前10个时间点,进行时间校正、头动校正。去除协变量以控制生理噪声,配准至蒙特利尔神经病学研究所标准空间,以3 mm×3 mm×3 mm的分辨率进行重采样,随后采用全宽半高为6的高斯平滑核进行平滑步骤。对预处理后的图像依次进行ALFF、fALFF值的计算,滤过频率为0.01~0.08 Hz。

1.6 统计学分析

       采用SPSS 26.0及Graphpad Prism 9软件进行统计学分析。采用柯尔莫戈洛夫-斯米诺夫检验法分析各计量资料是否符合正态分布,符合正态分布的计量资料用均数±标准差(x¯±s)表示,用两独立样本t检验进行比较,非正态分布的计量资料用中位数(上下四分位数)[MP25,P75)]表示;计数资料如性别采用χ2检验比较。采用FDR多重比较校正,P<0.05为差异有统计学意义。分析PTDM组与PTHC组在临床指标、认知功能方面的差异,记录差异有统计学意义的临床指标。采用SPM12进行双样本t检验,单个体素P<0.01,体素数>40,采用FWE多重比较校正,P<0.05为差异有统计学意义,与临床资料、神经心理学测试得分进行Pearson相关分析。

2 结果

2.1 临床资料及神经心理学测试结果的比较

       所有受试者的人口统计学、临床指标及认知相关测评结果见表12。PTDM组吸烟时间、舒张压、甘油三酯、高密度脂蛋白胆固醇、极低密度脂蛋白胆固醇及葡萄糖水平均与PTHC组的差异具有统计学意义(P<0.05),并通过FDR校正。两组在饮酒时间、红细胞、血红蛋白、红细胞压积得分上差异有统计学意义(P<0.05),但未通过FDR校正。两组在性别、年龄、受教育年限、BMI、收缩压、总胆固醇、低密度脂蛋白胆固醇、PSQI、PHQ-9、GAD-7、SAS、SDS、MMSE、MOCA、DST-straight back、DST-recite backwards、逻辑记忆Ⅰ(即刻)、逻辑记忆Ⅱ(延迟)、视觉空间记忆Ⅰ(即刻)、视觉空间记忆Ⅱ(延迟)得分上差异无统计学意义(P>0.05)(表1、2)。

表1  PTDM和PTHC两组人口学、临床检验指标的相关性
Tab. 1  Demographic and clinical test indicators in PTDM and PTHC
表2  PTDM和 PTHC两组神经心理学测试结果
Tab. 2  Cognitive test results in PTDM and PTHC

2.2 功能指标分析

2.2.1 两组ALFF值与fALFF比较

       根据两独立样本t检验的结果,PTDM组和PTHC组中ALFF和fALFF的分布模式如图1所示。PTDM组ALFF值在右侧小脑Ⅷ区(39,-54,-54)、右侧小脑Ⅷ区(15,-66,-54)及左侧小脑Ⅷ区(-12,-60,-60)显著低于PTHC组(P<0.05,FWE校正)(图1A1C表3)。PTDM组fALFF值在右侧舌回(18,-96,-21)、左侧小脑Ⅰ区(-33,-87,-24)显著低于PTHC组(P<0.05,FWE校正)(图1D1E表4)。PTDM组患者与PTHC组之间未发现ALFF和fALFF增高的区域。

图1  PTDM和PTHC两组ALFF值和fALFF值差异脑区。1A、1B、1C为两组ALFF值差异脑区,1D、1E为两组fALFF值差异脑区;P<0.05,FWE校正。PTDM:高原藏族糖尿病,PTHC:高原藏族健康对照;ALFF:低频振幅;fALFF:比率低频振幅。
Fig. 1  The difference in amplitude of low-frequency fluctuation (ALFF) and fractional amplitude of low-frequency fluctuations (fALFF) values between the plateau Tibetan diabetes mellitus (PTDM) and plateau Tibetan health control (PTHC) groups in brain regions. 1A, 1B and 1C are the brain regions with different ALFF values between two groups. 1D and 1E are the brain regions with different fALFF values between two groups. P<0.05, FWE corrected.
表3  PTDM和 PTHC两组ALFF值差异脑区
Tab. 3  Brain regions with different ALFF values
表4  PTDM和 PTHC两组fALFF值差异脑区
Tab. 4  Brain regions with different fALFF values

2.2.2 相关性分析

       Pearson相关分析显示,PTDM组患者双侧小脑Ⅷ区[左侧小脑Ⅷ区(r=0.376,P=0.006)、右侧小脑Ⅷ区包括(39,-54,-54)(r=0.411,P=0.002)、(15,-66,-54)(r=0.377,P=0.005)]ALFF值与年龄呈正相关;PTDM组患者左侧小脑Ⅷ区与低密度脂蛋白胆固醇(r=-0.283,P=0.049)、糖化血红蛋白(r=-0.320,P=0.028)、两小时血糖(r=-0.405,P=0.016)呈负相关(图2)。PTDM组患者右侧舌回fALFF值与年龄呈正相关(r=0.337,P=0.014),与SAS呈负相关(r=-0.399,P=0.012);PTDM组患者左侧小脑Ⅰ区fALFF值与吸烟时间呈正相关(r=0.407,P=0.006),与PSQI(r=-0.327,P=0.033)、SDS(r=-0.320,P=0.041)及PHQ-9(r=-0.339,P=0.035)呈负相关(图3)。PTHC组患者右侧小脑Ⅷ区(39,-54,-54)(r=0.336,P=0.016)、(15,-66,-54)(r=0.312,P=0.026)ALFF值与年龄呈正相关(图2)。

图2  PTDM和PTHC两组ALFF值差异脑区与临床和神经心理学测试结果的相关性散点图。2A:PTDM、PTHC组右侧小脑Ⅷ区(39,-54,-54)ALFF值与年龄呈正相关。2B:PTDM、PTHC组右侧小脑Ⅷ区(15,-66,-54)ALFF值与年龄呈正相关。2C:PTDM组左侧小脑Ⅷ区ALFF值与年龄呈正相关,与低密度脂蛋白胆固醇、糖化血红蛋白、两小时血糖呈负相关。PTDM:高原藏族糖尿病,PTHC:高原藏族健康对照。ALFF:低频振幅。
Fig. 2  Significant correlations between ALFFvalues and neuropsychological performances and different clinical variables in PTDM patients and PTHC. 2A: The ALFF values in the right cerebellar region Ⅷ (39, -54, -54) of the PTDM and PTHC groups were positively correlated with age. 2B: The ALFF values in the right cerebellar region Ⅷ (15, -66, -54) of the PTDM and PTHC groups were positively correlated with age. 2C: The ALFF value in the left cerebellar region Ⅷ of the PTDM group was positively correlated with age, and negatively correlated with low-density lipoprotein cholesterol, glycated hemoglobin, and 2-hour blood glucose. PTDM: plateau Tibetan type 2 diabetes mellitus, PTHC: plateau Tibetan health control; ALFF: amplitude of low-frequency fluctuations.
图3  PTDM和 PTHC 两组fALFF值差异脑区与临床和神经心理学测试结果的相关性散点图。3A:PTDM、PTHC组右侧舌回fALFF值与年龄呈正相关,与SAS呈负相关。3B:PTDM组左侧小脑Ⅰ区fALFF值与吸烟时间呈正相关,与PSQI、SAS、PHQ-9总分呈负相关。PTDM:高原藏族糖尿病;PTHC:高原藏族健康对照;fALFF:比率低频振幅;SAS:Zung氏焦虑自评量表;PSQI:匹兹堡睡眠质量指数量表;PHQ-9:患者健康问卷;SDS:抑郁自评量表。
Fig. 3  Significant correlations between fALFF values and neuropsychological performances and different clinical variables in PTDM patients and PTHC. 3A: The fALFF value of the right lingual gyrus in the PTDM and PTHC groups is positively correlated with age, and negatively correlated with SAS. 3B: The fALFF value in the left cerebellar region I of the PTDM group was positively correlated with smoking time, and negatively correlated with the total scores of PSQI, SAS, and PHQ-9. PTDM: plateau Tibetan type 2 diabetes mellitus; PTHC: plateau Tibetan health control; FALFF: frational amplitude of low-frequency fluctuations; SAS: Zung's Self Rating Anxiety Scale; PSQI: Pittsburgh Sleep Quality Index; PHQ-9: Patient Health Status Questionnaire-9; SDS: Self-Rating Depression Scale.

3 讨论

       本研究通过分析PTDM患者rs-fMRI中ALFF和fALFF局部功能指标,同时将差异脑区的ALFF和fALFF值与人口学资料、临床指标、神经心理学测试进行相关性分析,发现相较于PTHC,PTDM患者的双侧小脑、右侧舌回局部脑功能指标明显减低,并且PTDM患者差异脑区局部功能指标与年龄、血糖、血脂、吸烟时间及睡眠、焦虑、抑郁神经心理学测试具有相关性。该结果可能表明了PTDM患者脑功能和神经心理认知功能的变化,弥补了PTDM患者rs-fMRI局部功能指标差异的研究空白,为探索高原藏族糖尿病相关脑功能变化和糖尿病相关的认知功能下降提供了新见解。

3.1 PTDM组与PTHC组人口统计学信息、临床指标之间的差异

       本研究发现,PTDM组存在血压及血脂异常,且与吸烟相关。既往在T2DM合并主观认知功能下降患者的淀粉样蛋白β沉积和fALFF相关性研究中发现T2DM组高脂血症的患病率(89%)高于健康对照(health control, HC)组(22%)[20];T2DM组甘油三酯水平明显高于HC组,高密度脂蛋白胆固醇水平明显低于HC组[21]。以上研究结果均与本研究结果一致。这是由于糖尿病患者常易伴有血脂异常,包括高密度脂蛋白胆固醇水平降低,低密度脂蛋白胆固醇及甘油三酯的浓度增加[22]。另一方面由于与自主神经病变、夜间血压降低较少、基线心率较高及血压变异性较高等因素相关,糖尿病患者合并高血压的发生率是非糖尿病患者的2倍[23]。同时吸烟导致罹患T2DM风险增加[24, 25]。因此糖尿病人群易合并血压、血脂异常及受吸烟等生活习惯影响。

3.2 两组ALFF及fALFF值差异脑区及其与临床指标、神经心理学测试结果之间的关系

       小脑在运动协调、高级认知功能和情绪调节中具有重要作用[26],双侧小脑Ⅷ区属于默认模式网络,与记忆和认知功能密切相关[27]。有研究证明T2DM患者的小脑功能障碍与认知功能受损相关[26]。在本研究中,PTDM组小脑的神经元自发活动减弱,这与过去的研究结论相符[6,28],表明PTDM的rs-fMRI小脑局部活动的减低与糖尿病相关的认知功能障碍相关。

       糖尿病、高血糖以及代谢变化促使细胞衰老,从而诱导各类并发症的产生,如肾病、视网膜病变、血管病变和心血管疾病[29];同时,糖尿病患者更容易出现与年龄相关的疾病,如阿尔茨海默病、轻度认知障碍及心血管疾病等,这表明T2DM可能加速机体老化[30]。西藏高原人口随着生活方式改变及年龄增加更易患糖尿病[31]。在本研究中,PTDM组双侧小脑Ⅷ区ALFF值相较于同龄PTHC组下降,表明糖尿病可能导致PTDM组患者小脑神经元活动减弱程度更加显著。因此,糖尿病导致的神经病理生理改变或许加速了脑功能随年龄增大而产生异常的进程。

       糖尿病认知功能障碍的影响因素包括胰岛素抵抗、血脂异常、神经炎症、微管相关蛋白tau过度磷酸化和淀粉样蛋白(Aβ)异常累积[32]。LO等[33]发现由于T2DM患者糖代谢失调,脂肪蛋白酶产生的C3a肽会促进胰岛素分泌并维持其代偿机制。高海拔条件下(>4000米),血脂异常对血糖有明显影响:甘油三酯水平每增加1 mmol/L,空腹血糖水平增加0.907 mmol/L,而餐后葡萄糖水平增加1.703 mmol/L[34]。本研究中HbA1c水平与左侧小脑Ⅷ区ALFF值呈负相关,说明HbA1c水平影响PTDM患者的脑功能,这与许多研究的结论相似:HbA1c水平与认知功能呈负相关,包括记忆[35]、执行功能[36]、注意和信息处理速度[37]。GEIJSELAERS等[38]的一项系统性综述,更是证明在未发生认知障碍的T2DM受试者中,糖化血红蛋白水平增高与认知功能呈负相关。PTDM组患者左侧小脑Ⅷ区ALFF值与低密度脂蛋白胆固醇、糖化血红蛋白、两小时血糖呈负相关,表明糖脂代谢异常引起的糖尿病患者低密度脂蛋白胆固醇水平升高可能共同促成了糖尿病自发脑活动差异,与T2DM导致的认知功能改变相关,确切的机制仍需进一步探索。

       舌回负责视觉记忆,且其功能活动改变与认知能力受损相关[39]。多项研究发现,T2DM患者存在舌回异常的自发神经活动[8,39, 40, 41, 42]。白伟等[41]发现,糖尿病视网膜病变的患者视觉网络(包括双侧距状回、双侧舌回、双侧枕中回)ALFF值减低,并且左侧舌回 ALFF值与MMSE得分呈负相关,主要表现在视觉空间记忆认知过程的减退。PENG等[28]认为视觉空间功能障碍在T2DM中较为常见,不仅限于视觉功能的损害,枕叶自发神经活动减少也与认知功能受损相关[28,39,43]。在本研究中,PTDM组fALFF值在右侧舌回显著低于PTHC组,与SAS及两小时胰岛素呈负相关,说明PTDM患者可能存在潜在的视觉空间功能障碍及认知功能的损害,与既往大部分研究结论相符[6,39, 40]

       研究表明,T2DM和抑郁的关系是双向[44]。抑郁会使糖尿病的发病风险增加60%,而糖尿病相关的抑郁总相对风险为1.15[45]。有的研究认为,T2DM患者的抑郁评分明显高于健康受试者,提示患者可能有抑郁倾向[46]。睡眠的数量和质量显著影响2型糖尿病的发生风险[47]。FANG等[48]和JAUSSENT等[49]的研究说明,睡眠障碍和抑郁症之间存在双向关联,睡眠障碍是抑郁症患者最突出的症状,同时也是新发或复发性抑郁症的独立危险因素[49]。本研究得到的结果是,PTDM组患者左侧小脑Ⅰ区fALFF值与PSQI、PHQ-9总分呈负相关。说明在某种程度上,PTDM组患者左侧小脑Ⅰ区fALFF值的减低能够反映PTDM组患者睡眠质量降低与抑郁情绪调节功能受损的情况。

       本研究入组的PTDM和PTHC整体相对较为年轻,同时和病程相关[50],糖尿病对脑功能的影响往往先于具体症状出现,导致记忆等认知测试的结果差异不具有统计学意义。高原藏族T2DM患者存在rs-fMRI局部功能指标的差异脑区位于小脑和右侧舌回,与既往平原人群T2DM研究结果一致[39, 40],这些差异脑区与视觉、认知功能相关。同时,差异脑区的局部功能指标与患者年龄、血糖/糖化血红蛋白水平、认知功能、睡眠质量与焦虑抑郁情绪相关。

3.3 不足与展望

       本研究存在一些局限性:首先,本研究是一项横断面研究,无法评估PTDM患者脑功能与认知变化的关系,无法分析PTDM患者静息态异常脑活动与认知功能的纵向变化情况;其次,本研究病例数量较少,得到的结果需要更多相关研究证实。希望今后能够推进多中心、纵向研究,以及更多的病例样本,得到准确并具有可推广性的PTDM患者静息状态脑局部功能指标的相关结论,并进一步探索与汉族T2DM患者的差异,更加有助于全面理解高原藏族T2DM的神经病理生理机制。

4 结论

       综上所述,高原藏族T2DM患者静息状态下右侧舌回及双侧小脑的自发活动减低,并与衰老、血糖/糖化血红蛋白水平、认知功能减低、睡眠质量和焦虑、抑郁情绪调节异常相关,本研究通过局部功能指标的研究揭示了高原藏族T2DM这一特殊人群脑功能的改变,为从神经影像学角度进一步了解高原藏族T2DM相关认知障碍的机制提供全新可靠的见解。

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