A new magnetic resonance-based approach to assessment of pathology in early Alzheimer's disease Kristin James2, Steven Chance3, , Tim James2, Lance Farr2, James Rafferty2, Gareth Thomas2, David Chase2, Michael Brady3, Christopher Rodgers3, Peter Jezzard3, and Scott Grafton1 1University of California, Santa Barbara, United States, 2Acuitas Medical, Swansea, United Kingdom, 3University of Oxford, Oxford, United Kingdom Method Background Important biological fine structures are often well beyond the resolution limit of clinical imaging. This work is the extension of a technique developed for assessing sub-millimetre fine fibrotic structures in chronic liver disease to the ultra-fine neurological textures of healthy and diseased human cortical structure. Diffraction rather than imaging: Diffraction methods are routinely used in Materials Science to measure interatomic distances which cannot be readily imaged. A key feature of diffraction is that one or a few directions serve to characterize the structures (as indicated by*). MRI acquires k-Space data: MRI is mathematically analogous to diffraction. Acquiring onedimensional data in k-space rather than the entire matrix required for images provides a dramatic signal advantage over imaging – But Requires selecting an Inner volume for analysis. Method MR Scanning Protocol T1 and T2* contrast pulse sequences designed to reveal myelinated tracks, minicolumn arrangements of pyramidal cells, and microvasculature in the mid layers of the cortex. T1 contrast A&A 368, L38{L41 (2001)} 1µm * Left to right: myelin, Nissl, and vasculature stained cortical tissue showing highly oriented ultra-fine repetitive structures with spatial wavelengths in the range of 30 to 100 µm. Both the neuronal cells and the axon bundles are expected to change spacing and to segment and lose columnar coherence in response to AD progression. 3T MRI with 4 cm loop surface coil 1. Tri-axial localiser (30 seconds) 2. 3D 0.7mm isotropic MPRAGE (3 minutes) 3. Positioning internal volume in the mid layers of the cortex with the analysis direction along a gyrus (3 minutes) 4. T1 acquisition (4 minutes) 5. 3D image acquisition (3 minutes) 6. T2* acquisition (6 minutes) 7. 3D image generation (3 minutes) Image-Space MRI K-Space Comparison of white matter and grey matter spatial wavelength spectra obtained using T2* contrast indicates that we may be seeing changes in density of vasculature in these two different tissues, a lead in to observing disease progression in CVD. Custom pulse sequence: provides selective internal volume excitation. Repeated measurements provide statistics: Mean noise level and confidence interval r T1 contrast is expected to highlight the myelinated axon bundles in the cortex against the surrounding cellular parenchyma, hence producing spectra reflecting the spatial wavelengths of these bundles. Above, a reference image shows the positioning of the prismatic acquisition volume in a cortical fold and T1 contrast spatial wavelength spectra. The peaks visible on the spectrum near 38 microns show the resolution available with this technique. The dominant peak at approximately 75 microns, clearly visible in the overlaid spectra from successive points along the cortex, is consistent with axon bundle spacing's reported in the literature. Validation: Dorsolateral prefrontal cortex Analysis direction (r) aligned orthogonal to minicolumn structures. Acknowledgement Anterior lateral temporal lobe Mario Mendoza and Phil Beach, UCSB Dept. of Psychology for assistance in MRI scanning and volunteer recruiting. Conclusions The initial results of this pilot study demonstrate that an MR-based spatial wavelength technique is a viable means of assessing neural microstructure. In an early-stage sampling of subjects, the technique has proven its ability to resolve structural features within the brain near the cellular level. Correspondence with histology in human brain as well as from biologic phantoms has shown that the structural features resolved are of size ranges that suggest we are seeing cellular, axonal, and vascular structures and therefore would be able to resolve their disruption in AD and CVD. This offers the possibility of applying this technique for monitoring pathological changes in vivo with resolution previously only available with postmortem histology. The next step is to begin building statistics by comparison of a range of cognitive states. As neuronal structures in the cortex of pig brain are nearly identical to those in human brain, we have used porcine tissue as a biological phantom. Myeloarchitecture histology of porcine brain left, and overlaid structural wavelength spectra from successive points along the top of a cortical fold in a nearby region of the same brain, taken using T1 contrast . Note that the positions of the dominant peaks along a 2.5mm length of cortex are consistent with the spacing of the myelinated axon bundles seen in the histology image.