Scattering Angle Resolved Optical Coherence Tomography Detects Early Changes in 3xTg Alzheimer's Disease Mouse Model

Abstract

Clinical intensity-based optical coherence tomographic retinal imaging is unable to resolve some of the earliest changes to Alzheimer's disease (AD) neurons. The aim of this pilot study was to demonstrate that scattering-angle-resolved optical coherence tomography (SAR-OCT), which is sensitive to changes in light scattering angle, is a candidate retinal imaging modality for early AD detection. SAR-OCT signal data may be sensitive to changes in intracellular constituent morphology that are not detectable with conventional OCT. Methods: In this cross-sectional study, retinas of a triple transgenic mouse model of AD (3xTg-AD) were imaged alongside age-matched control mice (C57BL/6J) using SAR-OCT. A total of 32 mice (12 control, 20 3xTg-Ad) at four ages (10, 20, 30, and 45 weeks) were included in this cross-sectional study, and three retinal feature sets (scattering, thickness, and angiography) were examined between the disease and control groups. Results: AD mice had significantly increased scattering diversity (lower SAR-OCT C parameter) at the earliest imaging time (10 weeks). Differences in the C parameter between AD and control mice were diminished at later times when both groups showed increased scattering diversity. AD mice have reduced retinal thickness compared to controls, particularly in central regions and superficial layers. No differences in vascular density or fractional blood volume between groups were detected. Conclusions: SAR-OCT is sensitive to scattering angle changes in a 3xTg-AD mouse model and could provide early-stage biomarkers for neurodegenerative diseases such as AD. Translational Relevance: Clinical OCT systems may be modified to record SAR-OCT images for non-invasive retinal diagnostic imaging of patients with neurodegenerative diseases such as AD. Recent guidelines and criteria for diagnosing AD include a category for a symptomatic, pre-dementia phase termed "mild cognitive impairment due to AD" 4,5 ; however, even in this early disease state, significant pathophysiological changes are observed. 6 In fact, changes in the brain can begin more than 20 years prior to the onset of AD symptoms. 7-9 Early detection of AD is believed to represent the best path forward for

Retinal Aging in 3× Tg-AD Mice Model of Alzheimer's Disease

“…Several age-dependent cellular and molecular changes have been described in mouse retinas, such as, photoreceptor mislocalization (Sugita et al, 2020 ) and vascular and RPE changes (Hermenean et al, 2021 ). Regarding metrics captured by OCT, although some studies have found age-dependent alterations in mouse retinas, such as auto-fluorescence (Ferdous et al, 2021 ) and scattering diversity (Gardner et al, 2020 ), these cannot be directly compared with our results. Therefore, we can only speculate that some healthy age-dependent neural adaptations may be altered in transgenic animals.…”

OCT Imaging in Murine Models of Alzheimer’s Disease in a Systematic Review: Findings, Methodology and Future Perspectives

“…The expression of both transgenes is controlled by the mouse Thy1.2 promoter [ 33 , 40 , 43 ]. A total of six different studies have utilised OCT to analyse the retina in this model: Chiquita et al [ 44 ] conducted a longitudinal analysis, examining male mice at 4, 8, 12, and 16 months of age and comparing them with age-matched WT mice ( C57BL/6J ); Song et al [ 45 ] employed female 3xTg-AD mice and B6129SF2/J mice as WT group; Gardner et al [ 46 ] performed a cross-sectional study with 20 3xTg-AD mice (16 males and 4 females) at different ages (2, 4, 7 and 10 months), comparing them with 12 C57BL/6J mice (only males) as the control group; Ferreira et al [ 47 ] utilised the 3xTg-AD model to compare the effects of disease and aging with a normative database of the C57BL6/129S model, using male mice at various ages (1, 2, 3, and 4 months); Guimarães et al [ 48 ] analysed 60 male 3xTg-AD mice and 57 male C57BL6/129S mice at different ages (1, 2, 3, 4, 8, 12, and 16 months) in a longitudinal study; Batista et al [ 49 ] examined both eyes of 144 male mice, including 57 3xTg-AD mice and 57 WT mice, at various ages (1, 2, 3, 4, 8, 12, and 16 months). …”

Retinal inner nuclear layer thickness in the diagnosis of cognitive impairment explored using a C57BL/6J mouse model

“…Moreover, previous studies in mice and humans have shown that the thickness of various retinal layers may be decreased in patients diagnosed with AD, FTD and PD 19 – 23 . However, few studies have adequately investigated the association between the thickness of retinal layers with CI in a cognitively healthy population at baseline 24 , 25 .…”