Tau蛋白沉积与脑代谢物的关联性：N-乙酰天门冬氨酸与肌酸作为进展期阿尔茨海默病的潜在生物标志物

doi:10.12122/j.issn.1673-4254.2025.11.07

摘要/Abstract

摘要：

目的通过精确的空间映射，探索阿尔茨海默病（AD）患者Tau蛋白与氢质子磁共振波谱（¹H-MRS）所检测的脑内生化代谢物间的潜在关联。方法收集2022年4月~2024年12月南京市第一医院核医学科共64例AD Tau⁺患者（PT组）和29例健康志愿者（HC组）的¹⁸F-APN-1607 PET/MR脑显像及同步采集的多体素¹H-MRS数据，对PET/MR数据进行视觉分析和基于体素的分析，以研究AD患者Tau蛋白沉积模式。在¹H-MRS扫描视野内筛选有效体素，并记录各有效体素内的PET标准摄取值比率（SUVr）以及各代谢物水平（含代谢物比值）：N-乙酰天门冬氨酸（NAA）、胆碱（Cho）、肌酸（Cr）、NAA/Cr、Cho/Cr。通过对Tau PET视觉分析，将PT组内各有效体素分为Tau阳性体素（Tau⁺体素）和Tau阴性体素（Tau^-体素）。比较各组间PET和¹H-MRS指标的差异，并分析Tau⁺体素内代谢物水平（含代谢物比值）与Tau PET SUVr之间的相关性。结果在双侧额叶（30.07%）、顶叶（29.96%）、颞叶（21.07%）、枕叶（15.89%），PT组相较于HC组存在显著的Tau蛋白沉积。¹H-MRS扫描视野内共纳入有效体素2236个，PT组体素1422个（其中Tau⁺体素994个、Tau^-体素428个），HC组体素814个。相较于HC组，PT组的NAA水平降低、SUVr增高（P<0.05）。亚组分析结果显示，与Tau^-体素相比，Tau⁺体素的SUVr增高、Cr和Cho/Cr降低（P<0.05）；与HC组相比，Tau⁺体素的SUVr增高、Cr降低（P<0.05）；与HC组相比，Tau^-体素的NAA降低（P=0.004）。Cho和NAA/Cr在各亚组间的差异无统计学意义（P>0.05）。Tau⁺体素内NAA、Cho、Cr与SUVr呈负相关（P<0.001）。结论进展期AD患者脑内Tau蛋白沉积显著且和部分代谢物水平改变相关。NAA水平的降低在Tau蛋白沉积前期及早期阶段更明显，Cr水平的改变在Tau蛋白沉积区域更显著，提示NAA及Cr可以为AD患者脑内Tau蛋白沉积的潜在生物标志物，为AD的早期诊断和疗效评估提供依据。

关键词: 阿尔茨海默病, 正电子发射断层扫描/磁共振成像, Tau蛋白, ¹⁸F-APN-1607, N-乙酰天门冬氨酸

Abstract:

Objective To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy (¹H-MRS) in patients with advanced Alzheimer's disease (AD). Methods From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent ¹⁸F-APN-1607 PET/MR and simultaneously acquired multi-voxel ¹H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the ¹H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau⁺) voxels and Tau-negative (Tau^-) voxels of the AD patients were compared for PET and ¹H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau⁺ voxels were analyzed. Results Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau⁺ and 428 Tau^- voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau⁺ voxels had higher SUVr and lower Cr and Cho/Cr than Tau^-voxels (P<0.05). Compared with the control group, Tau⁺ voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau^- voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau⁺ voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001). Conclusion The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.

Key words: Alzheimer's disease, positron emission tomography/magnetic resonance imaging, Tau protein, ¹⁸F-APN-1607, N-acetylaspartate

李孝媛, 张逸悦, 顾雨铖, 陈霓红, 钱鑫宇, 张朋俊, 郝佳欣, 王峰. Tau蛋白沉积与脑代谢物的关联性：N-乙酰天门冬氨酸与肌酸作为进展期阿尔茨海默病的潜在生物标志物[J]. 南方医科大学学报, 2025, 45(11): 2350-2357.

Xiaoyuan LI, Yiyue ZHANG, Yucheng GU, Nihong CHEN, Xinyu QIAN, Pengjun ZHANG, Jiaxin HAO, Feng WANG. Association between Tau protein deposition and brain metabolites: N-acetylaspartate and creatine as potential biomarkers for advanced Alzheimer's disease[J]. Journal of Southern Medical University, 2025, 45(11): 2350-2357.

图/表 8

图1 1例AD患者的PET/MRS图像

Fig.1 PET/MRS imaging of a female AD patient (76 years old, education years: 0; MMSE: 0; MoCa: 0; CDR: 3). A: Coronal, sagittal, and axial localization images of MRS acquisition site, where the yellow box indicates the homogenization region, the white box denotes the MRS acquisition area, and the blue box outlines the selected voxel. B: Co-registered PET/MR fusion image at the same level as the MRS acquisition.

表1 PT组和HC组临床资料比较

Tab.1 Comparison of clinical information of the AD patients (PT group) and the healthy control (HC) group (Mean±SD)

Variables	PT group (n=64)	HC group (n=29)	P
Gender (male/female, n)	25/39	13/16	0.767
Age (year)	68.48±8.98	61.53±9.81	0.382
Education years (year)	9.46±3.56	11.94±3.05	0.440
MMSE score (point)	19.45±7.55	28.59±1.45	<0.001
MoCA score (point)	15.63±7.61	26.66±2.83	<0.001
CDR score (point)	0.96±0.70	0.02±0.09	<0.001

图2 1例HC和1例PT组AD患者的18F-APN-1607 PET/MR融合图像

Fig.2 18F-APN-1607 PET/MR fusion imaging of a healthy control individual and an AD patient. A-C: Axial, coronal, and sagittal PET/MR fusion images of the brain of a male healthy control individual (72 years old, education years: 12; MMSE: 28, MoCa: 29; CDR: 0), showing physiological uptake in the choroid plexus without significant deposition of Tau protein in the remaining cerebrum and cerebellum. D-F: Axial, coronal, and sagittal PET/MR fusion images of the brain of a female AD patient (58 years old, education years: 12; MMSE: 5; MoCa: 2; CDR: 2) with diffuse and heterogeneous Tau protein deposition in the bilateral frontal, parietal, temporal, and occipital cortical regions. The color bar in the figure represents SUV.

图3 基于体素的分析方法得到的PT组Tau蛋白沉积显著增加的区域

Fig.3 Regions of significantly increased Tau protein deposition in the PT group as determined by voxel-based analysis methods. The color bar in the figure represents the statistical t-values; L: Left cerebral hemisphere; R: Right cerebral hemisphere.

表2 PT组和HC组代谢物水平（含代谢物比值）和Tau PET SUVr组间比较结果

Tab.2 Inter-group comparison of metabolite levels (or ratios) and Tau PET standardized uptake values between PT group and HC group (Mean±SD)

Variables	PT group	HC group	P
Voxel (n)	1422	814	-
Cr	29.02±12.07	28.97±10.71	0.063
Cho	24.58±11.16	24.47±11.40	0.829
NAA	45.02±20.54	47.03±18.84	0.022
Cho/Cr	0.856±0.239	0.864±0.219	0.406
NAA/Cr	1.660±0.663	1.742±0.564	0.065
SUVr	1.604±0.877	0.902±0.212	<0.001

表3 PT组体素亚分组后代谢物水平（含代谢物比值）和Tau PET SUVr组间比较结果

Tab.3 Inter-group comparison of metabolite levels (or ratios) and Tau PET SUVr following subgrouping of PT group voxels (Mean±SD)

Variables	Tau⁺voxel	Tau^-voxel	HC voxel	P	P₁	P₂	P₃
Voxel (n)	994	428	814		-	-	-
Cr	27.11±11.92	29.84±12.05	28.97±10.71	<0.001	0.004	0.495	<0.001
Cho	24.90±10.92	23.82±11.66	24.47±11.40	0.242	-	-	-
NAA	45.82±20.17	43.17±21.28	47.03±18.84	0.005	0.596	0.004	0.065
Cho/Cr	0.844±0.246	0.882±0.209	0.864±0.219	0.014	0.212	0.592	0.015
NAA/Cr	1.676±1.380	1.622±0.588	1.742±0.564	0.119	-	-	-
SUVr	1.921±0.871	0.870±0.149	0.902±0.212	<0.001	<0.001	0.999	<0.001

表4 Tau+体素组内各代谢物水平（含代谢物比值）和Tau PET SUVr的相关性分析结果

Tab.4 Correlation analysis of metabolite levels (or ratios) and Tau PET SUVr in Tau+ voxel

Variables	r	P
Cr	-0.161	<0.001
Cho	-0.176	<0.001
NAA	-0.200	<0.001
Cho/Cr	-0.058	0.787
NAA/Cr	-0.009	0.069

图4 1例PT组AD患者的1H-MRS代谢物热图及18F-APN-1607 PET/MR融合图像

Fig.4 1H-MRS metabolite heatmap and 18F-APN-1607 PET/MR fusion image of an AD patient. A-E: Heat maps of NAA, Cho, Cr, NAA/Cr, and Cho/Cr, respectively. F:18F-APN-1607 PET/MR fusion image of the AD patient (female, 58 years old, education years: 12; MMSE: 5; MoCa: 2; CDR: 2). NAA, Cho and Cr are lower in the Tau protein deposition area, while NAA/Cr and Cho/Cr showed no significant differences between the Tau protein deposition area and the non-Tau protein deposition area.

参考文献 34

[1]	Gin A, Nguyen PD, Serrano G, et al. Towards early diagnosis and screening of Alzheimer's disease using frequency locked whispering gallery mode microtoroid biosensors[J]. Res Sq, 2024: rs.3.rs-4355995. doi：10.1038/s44328-024-00009-8
[2]	Peretti DE, Boccalini C, Ribaldi F, et al. Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline[J]. Brain, 2024, 147(12): 4094-104. doi：10.1093/brain/awae211
[3]	CliffordJr Jack, , Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup[J]. Alzheimers Dement, 2024, 20(8): 5143-69. doi：10.1002/alz.13859
[4]	Lu JY, Wang J, Wu J, et al. Pilot implementation of the revised criteria for staging of Alzheimer's disease by the Alzheimer's Association Workgroup in a tertiary memory clinic[J]. Alzheimers Dement, 2024, 20(11): 7831-46. doi：10.1002/alz.14245
[5]	Tahami Monfared AA, Byrnes MJ, White LA, et al. Alzheimer's disease: epidemiology and clinical progression[J]. Neurol Ther, 2022, 11(2): 553-69. doi：10.1007/s40120-022-00338-8
[6]	Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease[J]. Lancet, 2021, 397(10284): 1577-90. doi：10.1016/s0140-6736(20)32205-4
[7]	Stelzl LS, Pietrek LM, Holla A, et al. Global structure of the intrinsically disordered protein tau emerges from its local structure[J]. JACS Au, 2022, 2(3): 673-86. doi：10.1021/jacsau.1c00536
[8]	Zhao LH, Teng JL, Mai W, et al. A pilot study on the cutoff value of related brain metabolite in Chinese elderly patients with mild cognitive impairment using MRS[J]. Front Aging Neurosci, 2021, 13: 617611. doi：10.3389/fnagi.2021.617611
[9]	Valatkevičienė K, Levin O, Šarkinaitė M, et al. N-acetyl-aspartate and myo-inositol as markers of white matter microstructural organization in mild cognitive impairment: evidence from a DTI-¹H-MRS pilot study[J]. Diagnostics (Basel), 2023, 13(4): 654. doi：10.3390/diagnostics13040654
[10]	Kara F, Joers JM, Deelchand DK, et al. ¹H MR spectroscopy biomarkers of neuronal and synaptic function are associated with tau deposition in cognitively unimpaired older adults[J]. Neurobiol Aging, 2022, 112: 16-26. doi：10.1016/j.neurobiolaging.2021.12.010
[11]	Li L, Liu FT, Li M, et al. Clinical utility of ¹⁸F-APN-1607 tau PET imaging in patients with progressive supranuclear palsy[J]. Mov Disord, 2021, 36(10): 2314-23. doi：10.1002/mds.28672
[12]	Krix S, Wilczynski E, Falgàs N, et al. Towards early diagnosis of Alzheimer's disease: advances in immune-related blood biomarkers and computational approaches[J]. Front Immunol, 2024, 15: 1343900. doi：10.3389/fimmu.2024.1343900
[13]	Chang Y, Liu JJ, Xu XD, et al. Subcortical tau deposition and plasma glial fibrillary acidic protein as predictors of cognitive decline in mild cognitive impairment and Alzheimer's disease[J]. Eur J Nucl Med Mol Imaging, 2025, 52(4): 1496-509. doi：10.1007/s00259-024-07016-x
[14]	鲁佳荧, 蒋皆恢, 王敏, 等. 阿尔茨海默病患者脑内tau蛋白分布与认知组分相关性的PET显像研究[J]. 中国临床神经科学, 2020, 28(4): 396-404.
[15]	Qiao Z, Wang GH, Zhao XB, et al. Neuropsychological performance is correlated with tau protein deposition and glucose metabolism in patients with Alzheimer's disease[J]. Front Aging Neurosci, 2022, 14: 841942. doi：10.3389/fnagi.2022.841942
[16]	Xu XJ, Ruan WW, Liu F, et al. ¹⁸F-APN-1607 tau positron emission tomography imaging for evaluating disease progression in Alzheimer's disease[J]. Front Aging Neurosci, 2022, 13: 789054. doi：10.3389/fnagi.2021.789054
[17]	Matthews DC, Kinney JW, Ritter A, et al. Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients[J]. Alzheimers Dement (N Y), 2024, 10(3): e12490. doi：10.1002/trc2.12490
[18]	Ye JW, Wan HL, Chen SH, et al. Targeting tau in Alzheimer's disease: from mechanisms to clinical therapy[J]. Neural Regen Res, 2024, 19(7): 1489-98. doi：10.4103/1673-5374.385847
[19]	Waheed Z, Choudhary J, Jatala FH, et al. The role of tau proteoforms in health and disease[J]. Mol Neurobiol, 2023, 60(9): 5155-66. doi：10.1007/s12035-023-03387-8
[20]	Zhang SM, Crossley CA, Yuan Q. Neuronal vulnerability of the entorhinal cortex to tau pathology in Alzheimer's disease[J]. Br J Biomed Sci, 2024, 81: 13169. doi：10.3389/bjbs.2024.13169
[21]	Hu JX, Sha WC, Yuan SS, et al. Aggregation, transmission, and toxicity of the microtubule-associated protein tau: a complex comprehension[J]. Int J Mol Sci, 2023, 24(19): 15023. doi：10.3390/ijms241915023
[22]	Wang M, Wei M, Wang LY, et al. Tau protein accumulation trajectory-based brain age prediction in the Alzheimer's disease continuum[J]. Brain Sci, 2024, 14(6): 575. doi：10.3390/brainsci14060575
[23]	Stouffer KM, Chen C, Kulason S, et al. Early amygdala and ERC atrophy linked to 3D reconstruction of rostral neurofibrillary tau tangle pathology in Alzheimer's disease[J]. Neuroimage Clin, 2023, 38: 103374. doi：10.1016/j.nicl.2023.103374
[24]	Ma D, Fetahu IS, Wang M, et al. The fusiform gyrus exhibits an epigenetic signature for Alzheimer's disease[J]. Clin Epigenetics, 2020, 12(1): 129. doi：10.1186/s13148-020-00916-3
[25]	Hu JL, Zhang M, Zhang YY, et al. Neurometabolic topography and associations with cognition in Alzheimer's disease: a whole-brain high-resolution 3D MRSI study[J]. Alzheimers Dement, 2024, 20(9): 6407-22. doi：10.1002/alz.14137
[26]	Zhang M, Hu JL, Zhang YY, et al. Associations between Aβ deposition and neurometabolic alterations in Alzheimer's disease: Insights from hybrid 3D MRSI-PET imaging[J]. Alzheimers Dement, 2025, 21(6): e70332. doi：10.1002/alz.70332
[27]	Sheikh-Bahaei N, Chen M, Pappas I. Magnetic resonance spectroscopy (MRS) in Alzheimer's disease[J]. Methods Mol Biol, 2024, 2785: 115-42. doi：10.1007/978-1-0716-3774-6_9
[28]	Kara F, Kantarci K. Understanding proton magnetic resonance spectroscopy neurochemical changes using Alzheimer's disease biofluid, PET, postmortem pathology biomarkers, and APOE genotype[J]. Int J Mol Sci, 2024, 25(18): 10064. doi：10.3390/ijms251810064
[29]	Muñoz-Castro C, Serrano-Pozo A. Astrocyte-neuron interactions in Alzheimer's disease[J]. Adv Neurobiol, 2024, 39: 345-82. doi：10.1007/978-3-031-64839-7_14
[30]	Singh S, Khan S, Shahid M, et al. Targeting tau in Alzheimer's and beyond: insights into pathology and therapeutic strategies[J]. Ageing Res Rev, 2025, 104: 102639. doi：10.1016/j.arr.2024.102639
[31]	Olešová D, Dobešová D, Majerová P, et al. Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies[J]. J Neuroinflammation, 2024, 21(1): 78. doi：10.1186/s12974-024-03060-4
[32]	Živanović M, Aracki Trenkić A, Milošević V, et al. The role of magnetic resonance imaging in the diagnosis and prognosis of dementia[J]. Biomol Biomed, 2023, 23(2): 209-24. doi：10.17305/bjbms.2022.8085
[33]	Abbaspour F, Mohammadi N, Amiri H, et al. Applications of magnetic resonance spectroscopy in diagnosis of neurodegenerative diseases: a systematic review[J]. Heliyon, 2024, 10(9): e30521. doi：10.1016/j.heliyon.2024.e30521
[34]	Matsuoka K, Hirata K, Kokubo N, et al. Investigating neural dysfunction with abnormal protein deposition in Alzheimer's disease through magnetic resonance spectroscopic imaging, plasma biomarkers, and positron emission tomography[J]. Neuroimage Clin, 2024, 41: 103560. doi：10.1016/j.nicl.2023.103560