Share：
Share this content in WeChat
X
[Chinese] [PDF] 32 1
• Clinical Article •
Association between virtual spatial navigation impairment, plasma p-tau217 levels and hippocampal-entorhinal cortex volume in patients with mild cognitive impairment
LEI Yan  CHEN Qian  LONG Cong  DENG Qiming  ZHANG Xin  ZHANG Bing 

Cite this article as: LEI Y, CHEN Q, LONG C, et al. Association between virtual spatial navigation impairment, plasma p-tau217 levels and hippocampal-entorhinal cortex volume in patients with mild cognitive impairment[J]. Chin J Magn Reson Imaging, 2026, 17(4): 19-26. DOI:10.12015/issn.1674-8034.2026.04.003.


[Abstract] Objective To investigate the relationship between spatial navigation impairment, medial temporal lobe structural (e.g., the hippocampus and entorhinal cortex) volumes, and plasma phosphorylated tau 217 levels in individuals with early Alzheimer's disease (AD) using a virtual spatial navigation task, and to evaluate the classification performance of combined indicators for identifying early AD high-risk populations.Materials and Methods We enrolled 111 participants (70 normal controls, 41 mild cognitive impairment). All underwent virtual spatial navigation testing; 88 also completed structural MRI and plasma p-tau217 assessment. Hippocampal subfield and entorhinal cortex volumes were extracted using FreeSurfer. Group differences and intercorrelations among measures were examined, and ROC curves evaluated classification performance.Results Compared to the NC group, the MCI group demonstrated significant atrophy in the entorhinal cortex and several hippocampal subfields (dentate gyrus, CA3, CA4, subiculum), impaired spatial navigation performance, and elevated plasma p-tau217 levels. Both drop error (r = 0.259, P = 0.015) and rotation error (r = 0.292, P = 0.007) in the navigation task were positively correlated with plasma p-tau217 levels. Drop error was negatively correlated with volumes of the left dentate gyrus (r = -0.277, P = 0.011), CA4 (r = -0.290, P = 0.007), and subiculum (r = -0.264, P = 0.015). Plasma p-tau217 levels were also negatively correlated with volumes of the left dentate gyrus (r = -0.228, P = 0.037), CA4 (r = -0.251, P = 0.021), and subiculum (r = -0.254, P = 0.020). The area under the ROC curve (AUC) for spatial navigation alone in classifying MCI versus NC was 0.724. This increased to 0.822 when spatial navigation was combined with structural MRI and plasma biomarker data.Conclusions Spatial navigation impairment in MCI is associated with elevated plasma p-tau217 and atrophy of specific hippocampal subregions. Virtual spatial navigation may serve as a useful behavioral indicator for early AD detection. A multimodal approach combining navigation performance with brain structural and plasma biomarkers enhances classification performance, providing a more comprehensive basis for early identification and monitoring of AD.
[Keywords] mild cognitive impairment；virtual reality；spatial navigation；p-tau217；magnetic resonance imaging；hippocampal subregions；entorhinal cortex

LEI Yan1, 2, 3   CHEN Qian1, 2, 3   LONG Cong1, 2, 3   DENG Qiming1, 2, 3   ZHANG Xin1, 2, 3   ZHANG Bing1, 2, 3*  

1 Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

2 Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing 210008, China

3 Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

Corresponding author: ZHANG B, E-mail: zhangbing_nanjing@nju.edu.cn

Conflicts of interest   None.

Received  2026-01-06
Accepted  2026-03-19
DOI: 10.12015/issn.1674-8034.2026.04.003
Cite this article as: LEI Y, CHEN Q, LONG C, et al. Association between virtual spatial navigation impairment, plasma p-tau217 levels and hippocampal-entorhinal cortex volume in patients with mild cognitive impairment[J]. Chin J Magn Reson Imaging, 2026, 17(4): 19-26. DOI:10.12015/issn.1674-8034.2026.04.003.

[1]
2023 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2023, 19(4): 1598-1695. DOI: 10.1002/alz.13016.
[2]
GALLEGO-RUDOLF J, WIESMAN A I, PICHET BINETTE A, et al. Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults[J]. Nat Neurosci, 2024, 27(11): 2130-2137. DOI: 10.1038/s41593-024-01763-8.
[3]
JIA J, NING Y, CHEN M, et al. Biomarker Changes during 20 Years Preceding Alzheimer's Disease[J]. N Engl J Med, 2024, 390(8): 712-722. DOI: 10.1056/NEJMoa2310168.
[4]
GEORGAKAS J E, HOWE M D, THOMPSON L I, et al. Biomarkers of Alzheimer's disease: Past, present and future clinical use[J/OL]. Biomarkers in Neuropsychiatry, 2023, 8: 100063 [2026-01-05]. https://doi.org/10.1016/j.bionps.2023.100063. DOI: 10.1016/j.bionps.2023.100063.
[5]
OSSENKOPPELE R, PICHET BINETTE A, GROOT C, et al. Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline[J]. Nat Med, 2022, 28(11): 2381-2387. DOI: 10.1038/s41591-022-02049-x.
[6]
HOWETT D, CASTEGNARO A, KRZYWICKA K, et al. Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation[J]. Brain, 2019, 142(6): 1751-1766. DOI: 10.1093/brain/awz116.
[7]
IGARASHI K M. Entorhinal cortex dysfunction in Alzheimer's disease[J]. Trends Neurosci, 2023, 46(2): 124-136. DOI: 10.1016/j.tins.2022.11.006.
[8]
MAO D, GU Y. Multisensory coding of self-motion and its contribution to navigation[J]. Nat Rev Neurosci, 2025, 26(11): 715-732. DOI: 10.1038/s41583-025-00970-x.
[9]
COUGHLAN G, ZHUKOVSKY P, PUTHUSSERYPPADY V, et al. Functional connectivity between the entorhinal and posterior cingulate cortices underpins navigation discrepancies in at-risk Alzheimer's disease[J]. Neurobiol Aging, 2020, 90: 110-118. DOI: 10.1016/j.neurobiolaging.2020.02.007.
[10]
COUGHLAN G, DESOUZA B, ZHUKOVSKY P, et al. Spatial cognition is associated with levels of phosphorylated-tau and β-amyloid in clinically normal older adults[J]. Neurobiol Aging, 2023, 130: 124-134. DOI: 10.1016/j.neurobiolaging.2023.06.016.
[11]
SEGEN V, KABIR M R, STRECK A, et al. Path integration impairments reveal early cognitive changes in subjective cognitive decline[J/OL]. Sci Adv, 2025, 11(36): eadw6404 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/40901947. DOI: 10.1126/sciadv.adw6404.
[12]
COUGHLAN G, PUTHUSSERYPPADY V, LOWRY E, et al. Test-retest reliability of spatial navigation in adults at-risk of Alzheimer's disease[J/OL]. PLoS One, 2020, 15(9): e0239077 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/329609.30. DOI: 10.1371/journal.pone.0239077.
[13]
O'KEEFE J, DOSTROVSKY J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat[J]. Brain Res, 1971, 34(1): 171-175. DOI: 10.1016/0006-8993(71)90358-1.
[14]
PENG J J, THROM B, NAJAFIAN JAZI M, et al. Grid cells accurately track movement during path integration-based navigation despite switching reference frames[J]. Nat Neurosci, 2025, 28(10): 2092-2105. DOI: 10.1038/s41593-025-02054-6.
[15]
JAYAKUMAR R P, MADHAV M S, SAVELLI F, et al. Recalibration of path integration in hippocampal place cells[J]. Nature, 2019, 566(7745): 533-537. DOI: 10.1038/s41586-019-0939-3.
[16]
ORMOND J, O'KEEFE J. Hippocampal place cells have goal-oriented vector fields during navigation[J]. Nature, 2022, 607(7920): 741-746. DOI: 10.1038/s41586-022-04913-9.
[17]
BIERBRAUER A, KUNZ L, GOMES C A, et al. Unmasking selective path integration deficits in Alzheimer's disease risk carriers[J/OL]. Sci Adv, 2020, 6(35): eaba1394 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/32923622. DOI: 10.1126/sciadv.aba1394.
[18]
LACZÓ M, MARTINKOVIC L, LERCH O, et al. Different Profiles of Spatial Navigation Deficits In Alzheimer's Disease Biomarker-Positive Versus Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment[J/OL]. Front Aging Neurosci, 2022, 14: 886778 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/35721017. DOI: 10.3389/fnagi.2022.886778.
[19]
LACZÓ M, SVATKOVA R, LERCH O, et al. Spatial navigation questionnaires as a supportive diagnostic tool in early Alzheimer's disease[J]. iScience, 2024, 27(6): 109832[2026-01-05].https://pubmed.ncbi.nlm.nih.gov/38779476. DOI: 10.1016/j.isci.2024.109832
[20]
OLTMER J, WILLIAMS E M, GROHA S, et al. Neuron collinearity differentiates human hippocampal subregions: a validated deep learning approach[J/OL]. Brain Commun, 2024, 6(5): fcae296 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/39262825. DOI: 10.1093/braincomms/fcae296
[21]
SUN L L, REN P, LI Z P, et al. Advances in the MRI study of connectivity structure and functional mechanism of hippocampal subregions in humans[J]. Chinese Science Bulletin, 2021, 66(35): 4510-4123. DOI: 10.1360/tb-2021-0446.
[22]
BRAAK H, BRAAK E. Neuropathological stageing of Alzheimer-related changes[J]. Acta Neuropathol, 1991, 82(4): 239-259. DOI: 10.1007/BF00308809.
[23]
RIDLER T, WITTON J, PHILLIPS K G, et al. Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy[J/OL]. Elife, 2020, 9: e59045 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/33242304. DOI: 10.7554/eLife.59045.
[24]
ASH A, BAEK S R, SINGH S, et al. Tau Pathology in the Entorhinal-Hippocampal Circuit[J/OL]. Alzheimer's & Dementia, 2022, 18(S4): e066393 [2026-01-05]. https://alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.066393. DOI: 10.1002/alz.066393.
[25]
COLMANT L, QUENON L, HUYGHE L, et al. Rotation errors in path integration are associated with Alzheimer's disease tau pathology: a cross-sectional study[J/OL]. Alzheimers Res Ther, 2025, 17(1): 34 [2026-01-05]. https://doi.org/10.1186/s13195-025-01679-w. DOI: 10.1186/s13195-025-01679-w.
[26]
TANGEN G G, NILSSON M H, STOMRUD E, et al. Spatial Navigation and Its Association With Biomarkers and Future Dementia in Memory Clinic Patients Without Dementia[J/OL]. Neurology, 2022, 99(19): e2081-e2091 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/36028328. DOI: 10.1212/wnl.0000000000201106.
[27]
JACK C R, ANDREWS J S, BEACH T G, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup[J]. Alzheimers Dement, 2024, 20(8): 5143-5169. DOI: 10.1002/alz.13859.
[28]
ASHTON N J, BRUM W S, DI MOLFETTA G, et al. Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology[J]. JAMA Neurol, 2024, 81(3): 255-263. DOI: 10.1001/jamaneurol.2023.5319.
[29]
SHIMA S, OHDAKE R, MIZUTANI Y, et al. Virtual reality navigation for the early detection of Alzheimer's disease[J/OL]. Front Aging Neurosci, 2025, 17: 1571429 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/40908958. DOI: 10.3389/fnagi.2025.1571429.
[30]
LI X, WANG X, SU L, et al. Sino Longitudinal Study on Cognitive Decline (SILCODE): protocol for a Chinese longitudinal observational study to develop risk prediction models of conversion to mild cognitive impairment in individuals with subjective cognitive decline[J/OL]. BMJ Open, 2019, 9(7): e028188 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/31350244. DOI: 10.1136/bmjopen-2018-028188.
[31]
JAK A J, BONDI M W, DELANO-WOOD L, et al. Quantification of five neuropsychological approaches to defining mild cognitive impairment[J]. Am J Geriatr Psychiatry, 2009, 17(5): 368-375. DOI: 10.1097/JGP.0b013e31819431d5.
[32]
DESIKAN R S, SÉGONNE F, FISCHL B, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest[J]. Neuroimage, 2006, 31(3): 968-980. DOI: 10.1016/j.neuroimage.2006.01.021.
[33]
IGLESIAS J E, AUGUSTINACK J C, NGUYEN K, et al. A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI[J]. Neuroimage, 2015, 115: 117-137. DOI: 10.1016/j.neuroimage.2015.04.042.
[34]
BENJAMINI Y, HOCHBERG Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing[J]. Journal of the Royal Statistical Society Series B: Methodological, 1995, 57(1): 289-300.
[35]
DONG Q, SHENG Y, ZHU J, et al. MRI-Driven Longitudinal Studies of Hippocampal Alterations During the Initial Cognitive Decline[J]. IEEE J Transl Eng Health Med, 2025, 13: 98-110. DOI: 10.1109/jtehm.2024.3510429.
[36]
WOODWARD M, BENNETT D A, RUNDEK T, et al. The relationship between hippocampal changes in healthy aging and Alzheimer's disease: a systematic literature review[J/OL]. Front Aging Neurosci, 2024, 16: 1390574 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/39210976. DOI: 10.3389/fnagi.2024.1390574.
[37]
BERRON D, VOGEL J W, INSEL P S, et al. Early stages of tau pathology and its associations with functional connectivity, atrophy and memory[J]. Brain, 2021, 144(9): 2771-2783. DOI: 10.1093/brain/awab114.
[38]
ZHANG S, CROSSLEY C A, YUAN Q. Neuronal Vulnerability of the Entorhinal Cortex to Tau Pathology in Alzheimer's Disease[J/OL]. Br J Biomed Sci, 2024, 81: 13169 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/39435008. DOI: 10.3389/bjbs.2024.13169.
[39]
ZILIOLI A, PANCALDI B, BAUMEISTER H, et al. Unveiling the hippocampal subfield changes across the Alzheimer's disease continuum: a systematic review of neuroimaging studies[J]. Brain Imaging Behav, 2025, 19(1): 253-267. DOI: 10.1007/s11682-024-00952-0.
[40]
WAN S, WANG S, ZHANG X, et al. Causal relationship between hippocampal subfield volume and Alzheimer's disease: a mendelian randomization study[J]. Neurol Sci, 2025, 46(5): 2091-2102. DOI: 10.1007/s10072-024-07976-w.
[41]
XU J, TAN S, WEN J, et al. Progression of hippocampal subfield atrophy and asymmetry in Alzheimer's disease[J]. Eur J Neurosci, 2024, 60(8): 6091-6106. DOI: 10.1111/ejn.16543.
[42]
BEZGIN G, PASCOAL T A, THERRIAULT J, et al. Tau profiling across Alzheimer's disease staging reveals vulnerability to disease pathophysiology[J]. Eur J Nucl Med Mol Imaging, 2025, 52(11): 4281-4291. DOI: 10.1007/s00259-025-07257-4.
[43]
HANKO V, APPLE A C, ALPERT K I, et al. In vivo hippocampal subfield shape related to TDP-43, amyloid beta, and tau pathologies[J]. Neurobiol Aging, 2019, 74: 171-181. DOI: 10.1016/j.neurobiolaging.2018.10.013.
[44]
DEKRAKER J, KÖHLER S, KHAN A R. Surface-based hippocampal subfield segmentation[J]. Trends Neurosci, 2021, 44(11): 856-863. DOI: 10.1016/j.tins.2021.06.005.
[45]
COLMANT L, BIERBRAUER A, BELLAALI Y, et al. Dissociating effects of aging and genetic risk of sporadic Alzheimer's disease on path integration[J]. Neurobiol Aging, 2023, 131: 170-181. DOI: 10.1016/j.neurobiolaging.2023.07.025.
[46]
KOIKE R, SOEDA Y, KASAI A, et al. Path integration deficits are associated with phosphorylated tau accumulation in the entorhinal cortex[J]. Brain Commun, 2024, 6(1):fcad359 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/38347945. DOI: 10.1093/braincomms/fcad359.
[47]
FERREIRA P C L, BELLAVER B, POVALA G, et al. Evaluating Plasma p-tau217 as an Endpoint for Alzheimer Disease Clinical Trials[J]. Neurology, 2026, 106(1): e214441 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/41364889. DOI: 10.1212/wnl.0000000000214441.
[48]
HANSEEUW B J, BETENSKY R A, JACOBS H I L, et al. Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study[J]. JAMA Neurol, 2019, 76(8): 915-924. DOI: 10.1001/jamaneurol.2019.1424.
[49]
BECKER S, GRANERT O, TIMMERS M, et al. Association of Hippocampal Subfields, CSF Biomarkers, and Cognition in Patients With Parkinson Disease Without Dementia[J/OL]. Neurology, 2021, 96(6): e904-e915 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/33219138. DOI: 10.1212/wnl.0000000000011224.
[50]
BOUWMAN M M A, FRIGERIO I, LIN C P, et al. Hippocampal subfields: volume, neuropathological vulnerability and cognitive decline in Alzheimer's and Parkinson's disease[J/OL]. Alzheimers Res Ther, 2025, 17(1): 121 [2026-01-05]. https://doi.org/10.1186/s13195-025-01768-w. DOI: 10.1186/s13195-025-01768-w.
[51]
YING J, KEINATH A T, LAVOIE R, et al. Disruption of the grid cell network in a mouse model of early Alzheimer's disease[J/OL]. Nat Commun, 2022, 13(1): 886 [2026-01-05]. https://doi.org/10.1038/s41467-022-28551-x. DOI: 10.1038/s41467-022-28551-x.
[52]
OUCHI A, FUJISAWA S. Predictive grid coding in the medial entorhinal cortex[J]. Science, 2024, 385(6710): 776-784. DOI: 10.1126/science.ado4166.
[53]
LACZÓ M, SVACOVA Z, LERCH O, et al. Spatial navigation deficits in early Alzheimer's disease: the role of biomarkers and APOE genotype[J/OL]. J Neurol, 2025, 272(6): 438 [2026-01-05]. https://doi.org/10.1007/s00415-025-13151-8. DOI: 10.1007/s00415-025-13151-8.
[54]
DE FLORES R, LA JOIE R, CHÉTELAT G. Structural imaging of hippocampal subfields in healthy aging and Alzheimer's disease[J]. Neuroscience, 2015, 309: 29-50. DOI: 10.1016/j.neuroscience.2015.08.033.
[55]
HILL P F, BERMUDEZ S, MCAVAN A S, et al. Age differences in spatial memory are mitigated during naturalistic navigation[J/OL]. bioRxiv, 2023 [2026-01-05]. https://pubmed.ncbi.nlm.nih.gov/38445641. DOI: 10.1101/2023.01.23.525279.
[56]
WISSE L E M, DAUGHERTY A M, OLSEN R K, et al. A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?[J]. Hippocampus, 2017, 27(1): 3-11. DOI: 10.1002/hipo.22671.

PREV Study on brain structural magnetic resonance imaging characteristics and correlation with cognitive function in patients with atrial fibrillation-associated mild cognitive impairment
NEXT Effects of sham acupuncture on brain activity in migraine patients: A Meta-analysis of neuroimaging-based activation likelihood estimation
  


LINK


Tel & Fax: +8610-67113815    E-mail: editor@cjmri.cn