Abstract
Alzheimer's disease (AD) continuum is defined as a cascade of several neuropathological processes that can be measured using biomarkers, such as cerebrospinal fluid (CSF) levels of Aβ, p-tau, and t-tau. In parallel, brain anatomy can be characterized through imaging techniques, such as magnetic resonance imaging (MRI). In this work we relate both sets of measurements and seek associations between biomarkers and the brain structure that can be indicative of AD progression. The goal is to uncover underlying multivariate effects of AD pathology on regional brain morphological information. For this purpose, we used the projection to latent structures (PLS) method. Using PLS, we found a low dimensional latent space that best describes the covariance between both sets of measurements on the same subjects. Possible confounder effects (age and sex) on brain morphology are included in the model and regressed out using an orthogonal PLS model. We looked for statistically significant correlations between brain morphology and CSF biomarkers that explain part of the volumetric variance at each region-of-interest (ROI). Furthermore, we used a clustering technique to discover a small set of CSF-related patterns describing the AD continuum. We applied this technique to the study of subjects in the whole AD continuum, from the pre-clinical asymptomatic stages all the way through to the symptomatic groups. Subsequent analyses involved splitting the course of the disease into diagnostic categories: cognitively unimpaired subjects (CU), mild cognitively impaired subjects (MCI), and subjects with dementia (AD-dementia), where all symptoms were due to AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive cognitive and memory decline and specific neuropathological processes, namely extracellular beta-amyloid plaque deposition and intracellular neurofibrillary tangles accumulation [1]
We studied the relationship between brain morphology and the two underlying processes of aging and AD pathology
In this article we analyzed the relationship between brain morphology and markers of normal aging and AD, along the AD continuum
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive cognitive and memory decline and specific neuropathological processes, namely extracellular beta-amyloid plaque deposition and intracellular neurofibrillary tangles accumulation [1]. A recent paper [6] suggests a new research framework considering AD purely as a biological continuum, excluding clinical symptoms from its definition According to this framework the term “Alzheimer’s disease” is applied, regardless of the clinical manifestations, whenever there is evidence of pathologic deposits of both Aβ and tau in the brain, as manifested, for example, through AD cerebrospinal (CSF) core biomarkers: Abeta, phosphorylated Tau (ptau), and total Tau (t-tau) which reflect amyloid pathology, tau pathology, and neurofibrillary tangle neurodegeneration, respectively. Individuals with either Alzheimer pathologic change or Alzheimer’s disease belong to the so-called “Alzheimer’s continuum”, and these individuals may be in different clinical stages, from the cognitively unimpaired stage to the stage of dementia Similar to this criteria, the Food and Drug Administration (FDA) of the United States government proposed a 4-stage model [7] where stage 1 (no clinical impact) and stage 2 (subtle detectable abnormalities on sensitive neuropsychological measures) fall into the pre-AD category and stages 3 and 4 fall into the MCI and AD-dementia categories, respectively
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