In Vivo Optical Signatures of Neuronal Death in a Mouse Model of Alzheimer’s Disease

BACKGROUND There currently is a need for cost-effective, quantitative techniques to evaluate the gradual progression of Alzheimer's disease (AD). Measurement techniques based on diffuse optical spectroscopy can detect blood perfusion and brain cellular composition changes, through measuring the absorption (µa ) and reduced scattering (µs ') coefficients, respectively, using non-ionizing near-infrared light. Previous work has shown that brain perfusion deficits in an AD mouse model can be detected. The objective of this study was to determine if µs ' is sensitive to the inflammation and neuron death found in AD. METHODS We used spatial frequency domain imaging (SFDI) to form quantitative maps of µa and µs ' in 3-month old male CaM/Tet-DTA mice harboring transgenes for the doxycyline-regulated neuronal expression of diphtheria toxin. When doxycycline is removed from the diet, CaM/Tet-DTA mice develop progressive neuronal loss in forebrain neurons. Mice (n = 5) were imaged longitudinally immediately prior to and after 23 days of lesion induction, and µa and µs ' (30 wavelengths, 650-970 nm) were compared to properties obtained from Tet-DTA controls (n = 5). Neuron death and infiltration of inflammatory cells in brain cortical slices was confirmed with immunohistochemistry. RESULTS No significant difference in baseline scattering and absorption were measured between CaM/Tet-DTA mice and controls. After 23 days of lesion induction, brain cortical µs ' was 11-16% higher in the CaM/Tet-DTA mice than in controls (P < 0.03). Longitudinal imaging showed no significant difference in µs ' between the first and 23rd day of imaging in controls. Removing doxycycline from the diet was associated with a significant decrease in total hemoglobin concentrations (119 ± 9 µM vs. 91 ± 8 µM) (P < 0.05) in controls, but not in CaM/Tet-DTA mice. CONCLUSIONS Neuronal death and brain inflammation are associated with increased tissue scattering (µs ') and this optical biomarker may be useful in pre-clinical AD therapy evaluation or monitoring of disease progression in AD patients.