Association between Tau protein deposition and brain metabolites: N-acetylaspartate and creatine as potential biomarkers for advanced Alzheimer's disease

doi:10.12122/j.issn.1673-4254.2025.11.07

Abstract

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

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.

Figures/Tables 8

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.

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

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.

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.

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

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

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

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.

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