Tissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease.

Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as 'tauopathies', by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases.

Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.

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

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.

A viable isolated tissue system: a tool for detailed MR measurements and controlled perturbation in physiologically stable tissue.

In vivo magnetic resonance imaging (MRI) assessment of neuronal tissue is prone to artifacts such as movement, pulsatile flow, and tissue susceptibility. Furthermore, stable in vivo scans of over 3 h are difficult to achieve, experimental design is therefore limited. Using isolated tissue maintained in a viable physiological state can mitigate many of these in vivo issues. This work describes the fabrication and validation of an MRI compatible viable isolated tissue maintenance chamber. Parameters measured from maintained rat optic nerves did not change significantly over 10 h: (i) mean axon radius [electron microscopy--0 h: 0.75±0.46; 5 h: 0.74±0.35; 10 h: 0.76±0.35 µm (P>>0.05, t-test], (ii) action potentials [grease-gap electrophysiology--4.89±0.16 mv, (P>>0.05, Pearson test], and (iii) diffusion tensor imaging parameters [fractional anisotropy: 0.86±0.02 (P>>0.05, Pearson test), mean diffusivity: 1.48E-06±9.74E-08 cm2/s, (P>>0.05, Pearson test)]. In addition, a thorough diffusion-weighted MR protocol demonstrated the comparable stability of viable isolated and chemically fixed rat optic nerve. This MRI compatible viable isolated tissue system allows researchers to probe neuronal physiology in a controlled environment by limiting in vivo artifacts and allowing extended MRI acquisitions.

The importance of RF bandwidth for effective tagging in pulsed arterial spin labeling MRI at 9.4T.

The movement towards MRI at higher field strengths (>7T) has enhanced the appeal of arterial spin labeling (ASL) for many applications due to improved SNR of the measurements. Greater field strength also introduces increased magnetic susceptibility effects resulting in marked B(0) field inhomogeneity. Although B(0) field perturbations can be minimised by shimming over the imaging volume, marked field inhomogeneity is likely to remain within the labeling region for pulsed ASL (PASL). This study highlights a potential source of error in cerebral blood flow quantification using PASL at high field. We show that labeling efficiency in flow-sensitive alternating inversion recovery (FAIR) displayed marked sensitivity to the RF bandwidth of the inversion pulse in a rat model at 9.4T. The majority of preclinical PASL studies have not reported the bandwidth of the inversion pulse. We show that a high bandwidth pulse of > = 15 kHz was required to robustly overcome the field inhomogeneity in the labeling region at high field strength, which is significantly greater than the inversion bandwidth ~2-3 kHz used in previous studies. Unless SAR levels are at their limit, we suggest the use of a high bandwidth labeling pulse for most PASL studies.

Cardiac denervation in diabetes.

Cardiac parasympathetic damage is the earliest indicator of cardiac denervation in the diabetic. This was assessed in 35 diabetics by beat-to-beat variation expressed as Maximum-Minimum Heart Rate; 30/15 Ratio and the Standard Deviation of the R-R intervals. Both the 30/15 Ratio and the Maximum-Minimum Heart Rate methods showed good correlation of results and the drawbacks of each method were discussed. Although there was no good correlation between the duration of diabetes and impaired beat-to-beat variation, late complications of diabetes were associated with impaired autonomic function tests. The natural history and the importance of detection of diabetic autonomic neuropathy were both discussed.