P1–103: Imaging of TASTPM transgenic mice reveals progressive magnetic anomalies in the thalamus

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TASTPM transgenic (Tg) mice over–express the Alzheimer's disease (AD)–associated human proteins APP(K670N, M671L) × PS1(M146V) under the Thy–1 promoter. Cerebral Aβ is progressively deposited, and is widespread at 6 months. The Tg model will be most useful if plaque deposition is accompanied by neurodegeneration, as in AD patients. We repeatedly imaged TASTPM (n=7–10) and wildtype (WT, n=13) strains at 6, 9, 11 and 14 months of age to investigate if temporal neurodegenerative changes can be measured noninvasively in vivo. Experiments complied with GSK ethical and UK legal requirements. For MRI at 4.7T under gaseous anesthesia, the head was immobilised within the imaging coils; recovery was uneventful. A multi–slice gradient echo (TR/TE=2400/25ms) dataset was obtained, voxel size 78x78x312 μm. Local areas of signal loss are visible in the thalamus of Tg mice. Automated quantification of those areas consisted in brain segmentation and realignment to an in–house template using rigid–body registration (FSL, FMRIB, Oxford University, UK), followed by thresholding and volume measurement. A group minimum intensity map (MIM) was obtained to localise the signal loss territory. No signal loss is detected in the thalamus of WT mice. In Tg animals however, small discrete areas of signal loss (indicating presence of paramagnetic species) are detected robustly in animals from 9 months of age (p < 0.005). Within time points, the signal loss extent (arbitrary unit) varies greatly between animals (mean and SD: 179±134, 267±172 and 486±134 at 9, 11 and 14 months respectively). Within animals however, it increases systematically with age; changes are from 6 to 9 months 167±135 (p<0.005), from 9 to 11m 89±54 (p<0.001), and from 11 to 14m 153±93 (p<0.005). A linear regression of signal loss extent versus age gives R2 = 0.63. The MIM reveals that the signal loss is confined mainly to the VPM and VPL thalamic nuclei. Metal species, present in amyloid aggregations, could explain the thalamic changes. In humans, calcification is associated with AD and Down's syndrome. Where investigated, calcifications have been reported to include paramagnetic species. Could the changes reported here be used as a surrogate marker of neurodegeneration?

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