Down’s syndrome (DS), or trisomy 21, is a genetic disorder caused by the presence of an extra copy of chromosome 21 (Hsa21). DS individuals have a greater predisposition to early onset Alzheimer’s disease (AD), widely believed to be due to the extra dosage of the amyloid precursor protein (APP) gene: a risk factor gene for AD which lies on Hsa21.³ However, is it likely that other disease-modulating genes lie on Hsa21 which contribute to the increased incidence of AD in DS.⁴ Furthering our understanding of AD in individuals with DS may provide useful insights into the disease within the wider population.

In this work, we have sought to explore vascular alterations in the Tc1 mouse model of DS. The Tc1 mouse is an established model of DS which carries an almost-complete copy of Hsa21 but is not functionally trisomic for APP.⁵ The unique genetics of the Tc1 strain allow the study of DS without the effects of APP trisomy. Previous characterisation of the Tc1 mouse using structural MRI revealed proportional enlargement of the midbrain, and localised grey matter volume reductions within the cerebellum, olfactory bulb (OB) and foci within the thalamus;⁶ however, there has since been no further investigation into additional cerebral defects in this model. In this work, we have employed MRA in conjunction with tensor-based morphometry (TBM) to automatically characterise vascular alterations in the Tc1 mouse.

All imaging was performed with a 9.4T VNMRS horizontal bore scanner with a 120 mm diameter imaging gradient set (Agilent, UK) was used. A 72 mm birdcage RF coil was employed for RF transmission and a quadrature mouse brain surface coil (RAPID, Germany) was used for signal detection.

Generation of Tc1 mice has been previously reported (7). Female Tc1 (n=14) and wildtype controls (n=17) were imaged in vivo at 16 months. Angiograms were acquired using a 3D GE time-of-flight (TOF) MRA sequence with the following parameters: TR = 40 ms; TE = 2.5 ms; FA = 40°; NSA = 2; FOV = 15 mm × 15 mm × 20 mm; resolution=117 μm × 117 μm × 156μm.

TBM was employed to characterise vascular alterations in the Tc1 mouse using a previously described pipeline,⁸ including registration to a group average. An intensity threshold was applied in order to perform statistical tests on the vascular network.

Figure 1 shows the MIP of the averaged angiograms for wildtype and Tc1 mice. Many of the major feeding vessels can be readily delineated and identified using previously published MR angiograms of the mouse brain (9).

The average groupwise MRA images are shown in Figure 2, with TBM statistics overlaid. TBM detected significant contraction of the following arteries in the Tc1 mice: OpA, OlA, AzPA and ACA (Figure 2A-B). Conversely, expansion was detected in the following arteries: PCA, SCA and PPP (Figure 2C-D).

In this work, we have used MRA to explore vascular alterations in the Tc1 mouse. MRA is traditionally quantified manually, by visual inspection of apparent vessel alterations within a transgenic cohort.¹ However, it is possible to misinterpret flow artefacts (e.g. flow disturbances, signal voids) as vascular alterations.² Here, we have used TBM to evaluate alterations in the cerebral vessels, which may help mediate the confounding effects of flow artefacts, as these are averaged out during registration.¹

Our observations of alterations within the OpA, OlA, AzPA, and ACA may have arisen for a number of reasons, including narrowing or compression of the vessels, or reduced blood flow within these regions.⁹ Contraction of the OlA may relate to local volume decreases which have previously been observed in the OB in the Tc1 mouse.⁶ Deficits within this structure suggest an impaired sense of smell in the Tc1 mouse – a finding which has previously been observed in DS individuals and attributed to AD-related changes within the DS population.¹⁰ In the absence of AD neuropathology, our findings within the OB suggest that deficits may be present in the DS population prior to the development of AD.

Conversely, regions of artery expansion including the PCA and SCA, suggest increasing flow or widening of the vessels. Further work is required in order to corroborate these MRA findings with structural and/or functional alterations in this mouse, and the wider DS population.