Multiscale structural mapping of Alzheimer's disease neurodegeneration

The recently described biological framework of Alzheimer's disease (AD) emphasizes three types of pathology to characterize this disorder, referred to as the 'amyloid/tau/neurodegeneration' (A-T-N) status. The 'neurodegenerative' component is typically defined by atrophy measures derived from structural magnetic resonance imaging (MRI) such as hippocampal volume. Neurodegeneration measures from imaging are associated with disease symptoms and prognosis. Thus, sensitive image-based quantification of neurodegeneration in AD has an important role in a range of clinical and research operations. Although hippocampal volume is a sensitive metric of neurodegeneration, this measure is impacted by several clinical conditions other than AD and therefore lacks specificity. In contrast, selective regional cortical atrophy, known as the 'cortical signature of AD' provides greater specificity to AD pathology. Although atrophy is apparent even in the preclinical stages of the disease, it is possible that increased sensitivity to degeneration could be achieved by including tissue microstructural properties in the neurodegeneration measure. However, to facilitate clinical feasibility, such information should be obtainable from a single, short, noninvasive imaging protocol. We propose a multiscale MRI procedure that advances prior work through the quantification of features at both macrostructural (morphometry) and microstructural (tissue properties obtained from multiple layers of cortex and subcortical white matter) scales from a single structural brain image (referred to as 'multi-scale structural mapping'; MSSM). Vertex-wise partial least squares (PLS) regression was used to compress these multi-scale structural features. When contrasting patients with AD to cognitively intact matched older adults, the MSSM procedure showed substantially broader regional group differences including areas that were not statistically significant when using cortical thickness alone. Further, with multiple machine learning algorithms and ensemble procedures, we found that MSSM provides accurate detection of individuals with AD dementia (AUROC = 0.962, AUPRC = 0.976) and individuals with mild cognitive impairment (MCI) that subsequently progressed to AD dementia (AUROC = 0.908, AUPRC = 0.910). The findings demonstrate the critical advancement of neurodegeneration quantification provided through multiscale mapping. Future work will determine the sensitivity of this technique for accurately detecting individuals with earlier impairment and biomarker positivity in the absence of impairment.