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
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.
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)}
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)
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
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.
Analysis direction (r) aligned
orthogonal to minicolumn
Anterior lateral
temporal lobe
Mario Mendoza and Phil
Beach, UCSB Dept. of
Psychology for assistance in
MRI scanning and volunteer
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.