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 6

Comparison of baseline CSF Aβ42/40 and ADIC-NODDI in predicting longitudinal changes in cognition and dementia risk in CN and CI groups.

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Comparison of baseline CSF Aβ42/40 and ADIC-NODDI in predicting longitud...
Low, middle, and high values are the 25th, 50th, and 75th quantiles of the biomarker z score. The left panels show the longitudinal distributions of MMSE and CDR-SB anchored at the first CSF collection or dMRI scan of each subject, with CN and CI subjects color-coded. (A) Relationship between baseline Aβ42/40 levels and prospective MMSE scores, showing that a low Aβ42/40 ratio is significantly associated with faster MMSE decline in the CI group, but not in the CN group. (B) Relationship between baseline ADIC-NODDI and future MMSE scores, where lower ADIC-NODDI is also linked to faster MMSE decline in the CI group. (C) Relationship between baseline Aβ42/40 and prospective CDR-SB scores, with lower Aβ42/40 ratios significantly predicting a faster increase in CDR-SB in the CI group, but not in the CN group. (D) Lower baseline ADIC-NODDI is significantly associated with a faster increase in CDR-SB in the CI group, but not in the CN group. This analysis shows that both the Aβ42/40 and ADIC-NODDI biomarkers exhibit similar performances in predicting prospective cognitive and functional decline. Full results are shown in Supplemental Table 5.