Spatial frequency domain imaging of intrinsic optical property contrast in a mouse model of Alzheimer's disease

Abstract

Extensive changes in neural tissue structure and function accompanying Alzheimer's disease (AD) suggest that intrinsic signal optical imaging can provide new contrast mechanisms and insight for assessing AD appearance and progression. In this work, we report the development of a wide-field spatial frequency domain imaging (SFDI) method for non-contact, quantitative in vivo optical imaging of brain tissue composition and function in a triple transgenic mouse AD model (3xTg). SFDI was used to generate optical absorption and scattering maps at up to 17 wavelengths from 650 to 970 nm in 20-month-old 3xTg mice (n = 4) and age-matched controls (n = 6). Wavelength-dependent optical properties were used to form images of tissue hemoglobin (oxy-, deoxy-, and total), oxygen saturation, and water. Significant baseline contrast was observed with 13-26% higher average scattering values and elevated water content (52 ± 2% vs. 31 ± 1%); reduced total tissue hemoglobin content (127 ± 9 μM vs. 174 ± 6 μM); and lower tissue oxygen saturation (57 ± 2% vs. 69 ± 3%) in AD vs. control mice. Oxygen inhalation challenges (100% oxygen) resulted in increased levels of tissue oxy-hemoglobin (ctO(2)Hb) and commensurate reductions in deoxy-hemoglobin (ctHHb), with ~60-70% slower response times and ~7 μM vs. ~14 μM overall changes for 3xTg vs. controls, respectively. Our results show that SFDI is capable of revealing quantitative functional contrast in an AD model and may be a useful method for studying dynamic alterations in AD neural tissue composition and physiology.

Figure 1

(Left) Schematic of SFDI imaging of mouse brain through the intact skull. Non-ionizing broadband light is projected onto a spatial light modulator and light intensity patterns of different spatial frequencies are focused onto the mouse’s cranium. The reflectance is captured by a CCD camera with a tunable liquid crystal filter to select for specific wavelengths of light. (Right) Pixels in the region of interest (bregma to lambda and bilaterally to temporalis muscle attachments) are averaged for analyses

Figure 2

Representative optical property maps of control and Alzheimer’s brains taken with SFDI in vivo at normal air (21% O₂). Pixel values in the ROI were averaged for each mouse and wavelength-dependent reduced scattering and absorption coefficient spectra were plotted for control and 3xTg mice (group average ± group SE)

Figure 3

(a) Reduced scattering and (b) absorption spectra (group average ± group SE shown) were fit to the Mie scattering power law and for hemoglobin and water chromophores, respectively, with a least squares linear fit and R ² values were found. *p < 0.005, **p < 0.001

Figure 4

Representative dynamic time courses in Alzheimer’s (thin lines) and control mice (thick lines) of (a) oxy-hemoglobin (ctO₂Hb, dotted lines) and deoxy-hemoglobin (ctHHb, continuous lines), (b) oxygen saturation (O₂ sat), (c) total hemoglobin (Total Hb), and (d) reduced scattering coefficient at 670 nm (dotted lines) and 850 nm (continuous lines)

Figure 5

Hemoglobin and scattering at 670/850 nm magnitude changes between three min baselines during 21% O₂ and 100% O₂ were reduced in 3xTg mice compared to controls (group average ± group SE)