ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1609793
This article is part of the Research TopicAdvancing Neurodegenerative Disease Biomarkers: The Role of Neuroimaging in TDP-43 and Tau ProteinopathiesView all 3 articles
Multimodal DTI-ALPS and Hippocampal Microstructural Signatures Unveil Stage-Specific Pathways in Alzheimer's Disease Progression
Provisionally accepted
- 1Department of Radiology,Taixing People's Hospital, Taixing 225400 , Jiangsu province, China, Jiangsu, China
- 2Department of Nuclear Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Liaoning Province, China
- 3Nanjing Medical University, Nanjing, China
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Objective: Develop a multimodal biomarker framework integrating DTI-ALPS (Diffusion Tensor Imaging along the Perivascular Space), hippocampal diffusivity, and CSF profiles for staging Alzheimer's disease (AD) progression across the HC→MCI→AD continuum.Methods: Cross-sectional analysis of 60 age-matched participants (18 healthy controls (HC), 20 with mild cognitive impairment (MCI), and 22 with Alzheimer's disease (AD)) combining 3T MRI-derived biomarkers (bilateral hippocampal fractional anisotropy (FA) and mean diffusivity (MD), and DTI-ALPS). Cerebrospinal fluid (CSF) analysis (A β 42, p-tau181, t-tau), and cognitive assessments (MMSE, MoCA). Statistical analyses included ANOVA with Bonferroni correction, Pearson correlations, and ROC curve evaluation for disease classification.Results: DTI-ALPS exhibited a progressive decline (HC: 1.31±0.12 → MCI: 1.26±0.09 → AD: 0.87±0.19; p<0.001 for AD vs. HC/MCI). Bilateral FA reductions plateaued in MCI (left: 0.57 ± 0.11 vs. HC: 0.82 ± 0.07, p<0.001; right: 0.57 ± 0.11 vs. HC: 0.80 ± 0.07, p<0.001) without further progression at the AD stage. MD showed a right-lateralized progression (HC→MCI→AD: left 0.53→0.74→0.78, right 0.51→0.71→0.77; p<0.001), with a significant increase only in right MD from MCI to AD (p=0.014). CSF biomarkers revealed a hierarchical depletion of Aβ42 (AD: 370.7±145.9 vs. HC: 910.8±191.5 pg/mL, p<0.001) and accumulation of tau (t-tau: AD>MCI>HC, p<0.001). Receiver operating characteristic (ROC) analysis identified right hippocampal MD and t-tau as optimal classifiers for AD.The framework reveals distinct biomarker trajectories: DTI-ALPS distinguishes symptomatic AD from preclinical stages, while right hippocampal MD progression reflects tau-mediated neurodegeneration. Early FA reductions in MCI combined with CSF profiles suggest a hierarchical staging model: amyloid-associated perivascular dysfunction is associated with asymmetric tau-driven hippocampal degeneration. This multimodal approach provides clinically actionable biomarkers for AD progression monitoring.
Keywords: Alzheimer's disease, Mild Cognitive Impairment, DTI-ALPS index, hippocampal microstructure, fractional anisotropy, Mean diffusivity, CSF biomarkers
Received: 11 Apr 2025; Accepted: 18 Jul 2025.
Copyright: © 2025 Yu, Shen and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lijun Tang, Nanjing Medical University, Nanjing, China
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