Non-invasive Clinical Detection of Age-Related and Alzheimer’s Disease-Down Syndrome Dependent Changes in the Lens

Abstract

Purpose: : The hallmark pathology in Alzheimer’s disease (AD) is characterized by age-related deposition in the brain of amyloid-β peptides (Aβ) which eventually results in plaque formation. Aβ is a cleavage product derived from the amyloid precursor protein (APP) encoded on chromosome 21. DS is the most common chromosomal disorder in humans and carries 100% risk of early-onset AD due to chromosome 21 triplication. Triplication of the APP gene (21q21) results in increased expression of APP and Aβ overproduction. We discovered that Aβ accumulates in the supranuclear region of the lens in patients with AD (Goldstein et al., Lancet, 2003) and DS (Moncaster et al., PloS One, 2010). Here we present a non-invasive quantitative technique using quasi-elastic light scattering (QLS) analysis to detect and monitor AD-linked Aβ accumulation in the lens.

Methods: : In AD and DS lenses, Aβ accumulates as electron-dense intracellular aggregates (~5-100 nm) that distribute heterogeneously within the cytoplasm of supranuclear and deep cortical lens fiber cells. These Aβ lens aggregates qualify as Raleigh scattering centers that clinically manifest as distinctive specific supranuclear lens opacities that are phenotypically, anatomically, and biochemically distinguishable from common age-related nuclear cataracts. We use quasi-elastic light scattering (QLS) to detect and monitor these aggregates in vivo and in vitro.

Results: : QLS measurements were performed on DS subject and controls. We demonstrate early age-related increases in light scattering from the lens of subjects with DS compared to age-matched controls. In vitro and AD transgenic mouse studies confirm Aβ dose- and time-dependent increases in QLS light scattering.

Conclusions: : QLS can be used to detect early AD-linked Aβ pathology in the lenses of human subjects with Down Syndrome.

Keywords: aging • detection • laser