IMAGING OF THE BONE ARCHITECTURE IN THE CONTEXT OF ALZHEIMER DISEASE

Osteoarthritis (OA) and related symptom burden is associated with an increased risk for developing Alzheimer's Disease (AD). There is increasing evidence showing musculoskeletal changes occurring during AD. Falls and fractures are common in AD, making bone health management crucial. Early-stage AD has lower bone mineral density, which correlates with brain volume and cognitive decline. This warrants investigating the impact of changes in the bone beyond that tissue.

To identify structural and functional changes in the bone to visualize OA phenotyping changes in the preclinical models of AD.

To characterize the bone microarchitecture i.e. cortical and trabecular microarchitecture, Skyscan 1172 System, Bruker, Kontich, Belgium, V=60 kV, I=167 μA with rotation steps of 0.4° was used for µCT to scan the femur of 12-month-old PSEN1 KI/hAPP Tg+, FDD Tg+, MAPT P301S Tg+ and C57BL/6J mice, N = 20/group (equal number of male and female). We reconstructed the μCT scans using NRecon (Version 1.4.7.2, 2005-11, Microphotonics, Allentown, PA) calibrated to hydroxyapatite-mimicking phantoms (0.25 and 0.75 g/cm³ Ca-HA). We utilized NRecon (Version 1.4.7.2, 2005-11), Dataviewer (1.5.4.6, 2004-11, 2012-17), CTAn (1.18.4.0 +, 2003-11,200) to reconstruct, visualize, inspect, and analyze the scans, according to the manufacturer's protocols. We assessed trabecular properties (distal femur metaphysis region, beginning proximally 0.5 mm to the growth plate, extending proximally 1 mm) and cortical parameters (at the mid-diaphysis region) using a custom MATLAB code. Three-point bending tests were conducted using a servo-hydraulic test system (Test Resources Inc., Shakopee, MN, USA) to evaluate the biomechanical qualities.

Female Psen1 mutation(L166P) mice were found to have reductions in whole-body mineral density (BMD) and bone mineral content as early as one month and a sustained bone phenotype with age with loss in cortical and trabecular properties compared to age-and gendermatched wildtype control mice, whereas male mice did not (Fig.1A-C). In Tau P301S (PS19) Tg+ mice, the cortical and trabecular properties were altered mostly in males, whereas the biomechanical properties were altered both in male and female mice (Fig.1E). FDD Tg+ mice, which show amyloid, tau, and neuroinflammation, had alterations in cortical, trabecular and mechanical properties in both males and females at 12 months and increased bone resorpion (Fig.1F). Generally, among all murine cohorts, PSEN, APP (Fig. 1D) and Tau protein expression is observed in the bone, a potential crosstalk between the brain and the bone in AD.

Our imaging studies in preclinical models of AD suggest sex-specific changes in the bone during onset of amyloid pathology (Table1), indicating OA phenotype during AD.