In vivo imaging of tau pathology using multi-parametric quantitative MRI

Abstract

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

Tau protein aggregation is associated with cellular senescence in the brain

“…In brain tissue with tau pathology, cerebral blood flow was elevated in tau NFT ‐ Mapt 0/0 vehicle‐treated mice (21% whole brain, p  = 0.045; cortex, 48.7%, p  = 0.051, Supporting Information Figure S5b,c) and consistent with previous reports of tau NFT mice on a Mapt +/+ background (Wells et al, 2015). DQ improved aberrant cerebral blood flow in tau NFT ‐ Mapt 0/0 mice such that cerebral blood flow was no longer statistically different from controls (Supporting Information Figure S5b,c).…”

“…Aberrant cerebral blood flow is a functional defect that occurs in AD and tau NFT mice and is closely associated with cognitive impairment (Wells et al, 2015). In brain tissue with tau pathology, cerebral blood flow was elevated in tau NFT ‐ Mapt 0/0 vehicle‐treated mice (21% whole brain, p  = 0.045; cortex, 48.7%, p  = 0.051, Supporting Information Figure S5b,c) and consistent with previous reports of tau NFT mice on a Mapt +/+ background (Wells et al, 2015).…”

T1ρ relaxation time in brain regions increases with ageing: an experimental MRI observation in rats

“…It is expected that with the development of faster and more robust T1r techniques, T1r MR can be more widely applied in neuroimaging. 37,38,[45][46][47][48] In conclusion, an increase in T1r relaxation time was associated with age-related changes of the thalamus, hippocampus and frontal cortical regions of rat brain. A possible hypertensionrelated T1r increase in rat brain regions was also noted.…”

“…Although the biophysical/biochemical mechanism of ageingassociated T1r increase remains to be further investigated, together with other novel MRI techniques, such as chemical exchange saturation transfer and its variant chemical exchange imaging with spin-lock technique, these techniques might provide an early imaging biomarker for neurodegeneration diseases including AD, PD and dementia. 47,48 The age-related changes in T1r relaxation should also be taken into account in longitudinal studies in rodents. Further validation of ageing-associated T1r increase in vivo in the human brain is highly desired.…”

The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease

“…Mouse models provide useful tools for dissecting the relationship between white matter abnormalities and other pathologies, such as amyloid deposition (Song et al, 2004; Sun et al, 2005; Müller et al, 2013; Sun et al, 2014), abnormal tau hyperphosphorylation (Wells et al, 2015), vascular damage (Pathak et al, 2011), and the immune response (Tan et al, 1999; Frodl and Amico, 2014). To help understand the pathology and progression of AD, we have chosen to study the APPSwDI +/+ / mNos2 −/− (CVN-AD) mouse strain because it recapitulates multiple aspects of the human AD pathology, well described in previous publications (Wilcock et al, 2008; Colton et al, 2014; Kan et al, 2015).…”