Staging Neurodegeneration Across the AD Continuum

Abstract

AbstractBackgroundWhile amyloid and tau staging are ubiquitous in Alzheimer’s disease (AD), there are no equivalent staging techniques for AD‐related neurodegeneration. Currently, neurodegeneration in AD is commonly assessed with structural MRI measures such as hippocampal volume and cortical thickness. However, recent work suggests that markers for microstructural neurodegeneration derived from diffusion MRI (DWI) may provide crucial additional information related to the onset and progression of AD. Neurite density index (NDI) and return to origin probability (RTOP) are two DWI metrics that have shown promise for characterizing these microstructural alterations.To investigate the utility of DWI for staging neurodegeneration in AD, we implemented logistic regression to compare the abilities of NDI, RTOP, and hippocampal volume to predict AD dementia in 481 late‐middle‐aged participants on the AD continuum.Methods481 participants (383 cognitively unimpaired [CU], 68 Mild Cognitive Impairment [MCI], 30 AD) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged with T1‐weighted MRI and multi‐shell DWI. After delineating hippocampal volume, average NDI and RTOP values were extracted from the hippocampus and a whole brain white matter skeleton. All measures were fit to a logistic model with age, sex, and scanner as covariates.Corresponding ROC curves were used to derive cutoff values for NDI and RTOP by maximizing the Youden Index.ResultsBox plots and ROC curves are provided in Figures 1‐2 and cutoff values for each DWI metric are provided in Table 1. NDI and RTOP outperformed hippocampal volume in predicting AD across brain regions. The best performing marker was WM NDI (AUC = 0.905), followed closely by WM RTOP (AUC = .878). Meanwhile, hippocampal RTOP (AUC = 0.861) slightly outperformed hippocampal NDI (AUC = 0.844).ConclusionOur work adds to a growing body of literature which suggests that neuroimaging markers of brain microstructure may capture unique signatures of AD progression. Furthermore, the fact that both DWI measures performed best in whole brain WM reinforces WM degeneration as a core feature of AD pathophysiology. Future work will incorporate CSF and PET measures of amyloid and tau to better characterize AD‐specific neurodegeneration.