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
View: Text | PDF
Clinical Research and Public Health Clinical Research Neuroscience Public Health

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

×

Figure 2

Characterization of longitudinal trajectories of axonal integrity in CN and CI subjects.

Options: View larger image (or click on image) Download as PowerPoint
Characterization of longitudinal trajectories of axonal integrity in CN ...
(A) The longitudinal distribution of dMRI scans anchored at the first scan of each subject, with CN and CI groups color-coded. Both the CN and CI groups have similar longitudinal distributions, with many of the participants having over 3 years of follow-up dMRI measurements from baseline. (B) Representative ADI maps derived using the NODDI, C-NODDI, or SMI analyses, for 1 CN and 1 CI participant. Images are shown for the middle brain slice at 3 time points. (C) Results of the linear mixed-effects model of the association between whole-brain WM ADI and time (in years) given by, ADIij ~ β0 + βage × agei + βsex × sexi + βtime × timeij + βdiagnosis × diagnosisi + βtime×diagnosis × timeij × diagnosisi + bi + εij. Results are shown for each diagnosis group. CN and CI exhibit significant differences in axonal density/integrity, as measured using ADINODDI or ADIC-NODDI. While the CN group maintained a relatively constant axonal density/integrity over time, the CI group exhibited decreases in ADINODDI and ADIC-NODDI, that is, decreased axonal density/integrity, over time. In contrast, ADISMI showed a slight increase over time. Full statistical results are shown in Supplemental Table 1.