Early axonal degeneration linked to clinical decline in Alzheimer’s disease progression revealed with diffusion MRI
Zhaoyuan Gong, John P. Laporte, Alexander Y. Guo, Murat Bilgel, Jonghyun Bae, Noam Y. Fox, Angelique de Rouen, Nathan Zhang, Aaliya Taranath, Rafael de Cabo, Josephine M. Egan, Luigi Ferrucci, Mustapha Bouhrara, Alzheimer’s Disease Neuroimaging Initiative
Zhaoyuan Gong, John P. Laporte, Alexander Y. Guo, Murat Bilgel, Jonghyun Bae, Noam Y. Fox, Angelique de Rouen, Nathan Zhang, Aaliya Taranath, Rafael de Cabo, Josephine M. Egan, Luigi Ferrucci, Mustapha Bouhrara, Alzheimer’s Disease Neuroimaging Initiative
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Early axonal degeneration linked to clinical decline in Alzheimer’s disease progression revealed with diffusion MRI

Abstract

BACKGROUND Axonal degeneration is believed to be an early hallmark of Alzheimer’s disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using a dMRI-derived axonal density index (ADI).METHODS Longitudinal dMRI, CSF, and PET data from the ADNI study were analyzed, including 117 subjects that were cognitively normal (CN) and 88 that were cognitively impaired (CI), consisting of 74 individuals with mild cognitive impairment (MCI) and 14 with AD. Linear mixed-effects models examined group differences and associations between baseline and longitudinal changes in ADI, CSF, or PET biomarkers and clinical outcomes. Results derived from larger CSF (n = 527) and PET (tau-PET: n = 870; amyloid-PET: n = 1,581) datasets are also presented.RESULTS Compared with the CN group, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (P < 10–6). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: P = 0.03; CDR-SB: P < 10–4), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: P = 0.001; CDR-SB: P < 10–12). Compared with CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; this association was observed only with amyloid-PET, but not CSF, biomarkers.CONCLUSION Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring.TRIAL REGISTRATION ClinicalTrials.gov NCT00106899.FUNDING This work was supported by the National Institute on Aging Intramural Research Program.

Authors

Zhaoyuan Gong, John P. Laporte, Alexander Y. Guo, Murat Bilgel, Jonghyun Bae, Noam Y. Fox, Angelique de Rouen, Nathan Zhang, Aaliya Taranath, Rafael de Cabo, Josephine M. Egan, Luigi Ferrucci, Mustapha Bouhrara, Alzheimer’s Disease Neuroimaging Initiative

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Figure 5

Comparison of CSF and PET biomarkers and ADIC-NODDI in differentiating longitudinal trajectories between the CN and CI groups.

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Comparison of CSF and PET biomarkers and ADIC-NODDI in differentiating l...
Analyses were restricted to participants with both CSF or PET biomarkers and dMRI. The comparison was restricted to ADIC-NODDI, as it is the best-performing dMRI biomarker in differentiating axonal degeneration trajectories between CN and CI in the previous analyses. (A–E) Longitudinal data distributions for the 3 CSF biomarkers of AD pathology, tau, pTau181, and Aβ42/40, and the 2 PET biomarkers of AD pathology, amyloid-PET and tau-PET. Except for tau-PET, the trajectories of these CSF and PET biomarkers show no significant differentiation over time between the CN and CI groups. (F–J) Longitudinal dMRI data distribution for the ADIC-NODDI biomarker from the same participants included in the above CSF or PET analyses, for each CSF or PET biomarker. In contrast to CSF and PET biomarkers, the ADIC-NODDI trajectories reveal significant differentiation between diagnosis groups, demonstrating the superior sensitivity of ADIC-NODDI in detecting group differences over time compared with CSF and PET biomarkers of AD pathology. Full results are shown in Supplemental Table 4.