Ultrashort echo time magnetization transfer imaging of myelin in APP knock-in mice

Myelin integrity is increasingly recognized as a potential factor in Alzheimer's disease (AD) pathology, making accurate quantification of myelin essential for elucidating its role in the progression of the disease. This study aims to evaluate the potential of ultrashort echo time magnetization transfer (UTE-MT) imaging for assessing myelin-related alterations in an APP knock-in mouse model of AD (hereafter referred to as APPKI mice).

Eighteen APPKI mice (∼14 months; 9 females/9 males) and fourteen age-matched wild-type C57BL/6 (WT) (8 females/6 males) were scanned on a 3T Bruker scanner. Two sets of UTE-MT data (TR=80 ms, TE=0.026 ms) were acquired with an MT pulse power of 1500° (θ=1500°) and frequency offset of 2 kHz (Δf = 2 kHz) (MT_on), and with θ=500° and Δf = 50 kHz (MT_off), respectively. UTE-MT ratio (UTE-MTR) maps, calculated as (MT_off - MT_on)/MT_off, were generated for comparing APPKI and WT mice. Luxol Fast Blue (LFB) staining was employed to quantify myelin density in both the APPKI and WT groups by measuring average optical density (AOD) in the corpus callosum (CC) and hippocampus. A fear conditioning paradigm was conducted to assess cognitive function. Students' t-tests were used to compare UTE-MTR and AOD values, as well as freezing behavior between APPKI and WT groups. Furthermore, Pearson's correlation was used to quantify the association between UTE-MTR and AOD measurements.

The UTE-MTR values showed a significant reduction in the APPKI group compared to the WT group in both the CC (0.401±0.010 vs. 0.416±0.006, p < 0.0001) and the hippocampus (0.334±0.012 vs. 0.343±0.006, p < 0.05). Histological validation via LFB staining confirmed these findings, revealing a significantly lower AOD in APPKI mice across the same regions (p < 0.05). Pearson correlation analysis demonstrated a positive association between UTE-MTR and AOD in the corpus callosum for the APPKI group (r = 0.8174, P = 0.0132), while no significant correlation was observed in the hippocampus in either group. Additionally, APPKI mice exhibited significant impairments in fear learning, contextual memory recall, and cue memory recall compared with WT controls (p < 0.05), further supporting myelin-related cognitive deficits in this model.

Our findings suggest that UTE-MTR is a promising tool for detecting myelin-related changes in APPKI mice, with potential to monitor myelin alterations and cognitive deficits associated with AD pathological progression and to evaluate therapeutic efficacy in AD research.