Abstract
Purpose :
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by beta-amyloid (Aβ) pathology and progressive irreversible cognitive decline in AD. However, there is a long asymptomatic, pre-clinical phase during which it is predicted vascular dysfunction occurs. As the neural retina is an extension of the CNS and exhibits AD pathology we propose to use a custom murine Laser Speckle Contrast Imaging (LSCI) instrument to non-invasively assess whether retinal hemodynamics are altered in late stage disease and identify potential biomarkers of AD.
Methods :
A cohort of 16 month old 5xFAD (n=4) mice and littermate C57Bl/6j controls (n=6) were imaged with retinal LSCI at 376.2 Hz with 2.5 ms exposure for 1000 frames. Images underwent spatial averaging in a 5x5 local pixel neighborhood before applying a lowpass filter at the third harmonic of heart rate identified by fast Fourier transformation. A custom algorithm was used to identify hemodynamic features from the averaged pulse waveform. One 5xFAD mouse was imaged with magnetic resonance imaging (MRI) before euthanasia via cardiac perfusion for immunohistological comparison against a littermate control.
Results :
LSCI analyses included an average of 11±3 pulses per animal. Pulse and peak intervals were significantly elongated. Pulsatility (0.059 vs 0.033) and resistance indices (0.055 vs 0.031) were both increased in 5xFAD cohorts compared to controls. All comparisons were statistically significant on Mann-Whitney U analysis (p=<0.05). Frontal lobe immunohistology confirmed AD pathology in the 5xFAD mouse, however pathology was not visible on MRI.
Conclusions :
Several alterations to the retinal hemodynamic waveform were measured in 5xFAD mice by LSCI compared to age-matched litter mate controls.. The increase to both pulsatility and resistance indices may be particularly useful hemodynamic metrics of AD, where similar alterations have been observed in the cortex and the direction of change is expected to be opposite of that observed in common comorbidities, such as diabetes. Importantly, altered hemodynamics in 5xFAD mice coincided with AD progression seen in histology but manifested before pathology was detectable on MRI. This project produced the first evidence that there exist hemodynamic changes in AD detectable quickly and non-invasively via retinal LSCI, potentially earlier than other clinical diagnostic tools.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.