David M. Doddrell

Dynamics of Gray Matter Loss in Alzheimer's Disease

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimers disease (AD). The loss pattern was visualized in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, sparing sensorimotor cortices. The shifting deficits were asymmetric (left hemisphere > right hemisphere) and correlated with progressively declining cognitive status (p< 0.0006). Novel brain mapping methods allowed us to visualize dynamic patterns of atrophy in 52 high-resolution magnetic resonance image scans of 12 patients with AD (age 68.4 ± 1.9 years) and 14 elderly matched controls (age 71.4 ± 0.9 years) scanned longitudinally (two scans; interscan interval 2.1 ± 0.4 years). A cortical pattern matching technique encoded changes in brain shape and tissue distribution across subjects and time. Cortical atrophy occurred in a well defined sequence as the disease progressed, mirroring the sequence of neurofibrillary tangle accumulation observed in cross sections at autopsy. Advancing deficits were visualized as dynamic maps that change over time. Frontal regions, spared early in the disease, showed pervasive deficits later (>15% loss). The maps distinguished different phases of AD and differentiated AD from normal aging. Local gray matter loss rates (5.3 ± 2.3% per year in AD v 0.9 ± 0.9% per year in controls) were faster in the left hemisphere (p < 0.029) than the right. Transient barriers to disease progression appeared at limbic/frontal boundaries. This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.

Mapping hippocampal and ventricular change in Alzheimer disease

We developed an anatomical mapping technique to detect hippocampal and ventricular changes in Alzheimer disease (AD). The resulting maps are sensitive to longitudinal changes in brain structure as the disease progresses. An anatomical surface modeling approach was combined with surface-based statistics to visualize the region and rate of atrophy in serial MRI scans and isolate where these changes link with cognitive decline. Sixty-two [corrected] high-resolution MRI scans were acquired from 12 AD patients (mean [corrected] age +/- SE at first scan: 68.7 +/- 1.7 [corrected] years) and 14 matched controls (age: 71.4 +/- 0.9 years) [corrected] each scanned twice (1.9 +/- 0.2 [corrected] years apart, when all subjects are pooled [corrected] 3D parametric mesh models of the hippocampus and temporal horns were created in sequential scans and averaged across subjects to identify systematic patterns of atrophy. As an index of radial atrophy, 3D distance fields were generated relating each anatomical surface point to a medial curve threading down the medial axis of each structure. Hippocampal atrophic rates and ventricular expansion were assessed statistically using surface-based permutation testing and were faster in AD than in controls. Using color-coded maps and video sequences, these changes were visualized as they progressed anatomically over time. Additional maps localized regions where atrophic changes linked with cognitive decline. Temporal horn expansion maps were more sensitive to AD progression than maps of hippocampal atrophy, but both maps correlated with clinical deterioration. These quantitative, dynamic visualizations of hippocampal atrophy and ventricular expansion rates in aging and AD may provide a promising measure to track AD progression in drug trials.

Loss of connectivity in Alzheimer's disease: an evaluation of white matter tract integrity with colour coded MR diffusion tensor imaging

A NOVEL MRI METHOD diffusion tensor imaging—was used to compare the integrity of several white matter fibre tracts in patients with probable Alzheimers disease. Relative to normal controls, patients with probable Alzheimers disease showed a highly significant reduction in the integrity of the association white matter fibre tracts, such as the splenium of the corpus callosum, superior longitudinal fasciculus, and cingulum. By contrast, pyramidal tract integrity seemed unchanged. This novel finding is consistent with the clinical presentation of probable Alzheimers disease, in which global cognitive decline is a more prominent feature than motor disturbance.

Proton‐polarization transfer enhancement of a heteronuclear spin multiplet with preservation of phase coherency and relative component intensities

The DEPT pulse sequence (π/2)(H,y)−(2J)−1−π(H), (π/2)(C,x)−(2J)−1 −ϑ(H,x)π(C)−(2J)−1−(acquire 13C) is analyzed theoretically for a variable ϑ pulse for three spin systems: CH, CH2, and CH3. It is shown that the pulse train produces an enhanced distortion‐free 13C signal which has the following characteristics: (a) there is phase coherency within and between the components of the 13C multiplets; (b) the enhancements vary with ϑ as (γH/γC)sin ϑ for CH, (γH/γC)sin 2ϑ for CH2, and (3γH/4γC) (sin ϑ+sin 3ϑ) for CH3. Experimental evidence is provided for these predictions. An important application of the DEPT pulse train is for the generation of both individual proton‐coupled and proton‐decoupled 13C methine (CH), methylene (CH2), and methyl (CH3) subspectra. This can be readily achieved by forming suitable combinations of DEPT spectra determined at ϑ = (π/4), (π/2), and (3π/4). Such spectral editing is less sensitive to variations in J values than the INEPT pulse sequence. Signal enhancement for 195Pt and 29Si ...

AN EVALUATION OF THE TIME DEPENDENCE OF THE ANISOTROPY OF THE WATER DIFFUSION TENSOR IN ACUTE HUMAN ISCHEMIA

We have performed MRI examinations to determine the water diffusion tensor in the brain of six patients who were admitted to the hospital within 12 h after the onset of cerebral ischemic symptoms. The examinations have been carried out immediately after admission, and thereafter at varying intervals up to 90 days post admission. Maps of the trace of the diffusion tensor, the fractional anisotropy and the lattice index, as well as maps of cerebral blood perfusion parameters, were generated to quantitatively assess the character of the water diffusion tensor in the infarcted area. In patients with significant perfusion deficits and substantial lesion volume changes, four of six cases, our measurements show a monotonic and significant decrease in the diffusion anisotropy within the ischemic lesion as a function of time. We propose that retrospective analysis of this quantity, in combination with brain tissue segmentation and cerebral perfusion maps, may be used in future studies to assess the severity of the ischemic event.

Use of spherical harmonic deconvolution methods to compensate for nonlinear gradient effects on MRI images.

Spatial encoding in MR techniques is achieved by sampling the signal as a function of time in the presence of a magnetic field gradient. The gradients are assumed to generate a linear magnetic field gradient, and typical image reconstruction relies upon this approximation. However, high‐speed gradients in the current generation of MRI scanners often sacrifice linearity for improvements in speed. Such nonlinearity results in distorted images. The problem is presented in terms of first principles, and a correction method based on a gradient field spherical harmonic expansion is proposed. In our case, the amount of distortion measured within a typical field of view (FOV) required for head imaging is sufficiently large that without the use of some distortion correction technique, the images would be of limited use for stereotaxy or longitudinal studies, where precise volumetric information is required. Magn Reson Med 52:115–122, 2004.

Proton polarization transfer enhancement for a nucleus with arbitrary spin quantum number from n scalar coupled protons for arbitrary preparation times

Abstract Polarization transfer enhancement of the NMR resonance from a nucleus with spin quantum number l (l = 1 2 , 1, 3 2 , …) from n scalar coupled protons using the pulse sequence (90 x H)-τ-(180 x H)(180 x I)-τ-(90 y H)(90 x I)-Δ-(acquire with or without H decoupling) is studied theoretically. It is shown that the enhancement of the components of the I multiplet varies with τ as Σ m I m I sin (4 πJm I τ ) where J is the scalar coupling constant and m I takes the values l, l - l, …, -l . Values of τ opt which result in the maximum enhancement are calculated, as well as the size of these maximum enhancements. Values of Δ opt which yield the maximum decoupled signal are also computed, along with the maximum decoupled enhancements. The theory is confirmed experimentally for l = 3 2 and l = 3 by studying proton polarization transfer spectra of the 10 B and 11 B resonances in NaBH 4 .

Heisenberg vector model for precession via heteronuclear scalar coupling

Abstract Simple vector models have been considered as useful heuristic descriptions of the behavior of magnetization vectors of nuclei under the influence of heteronuclear scalar coupling during some straightforward multipulse sequences. However, it is generally held in the literature that the rigorous quantum-mechanical evolution should be treated by a density matrix approach, particularly where neither of the nuclei involved is in a pure z -spin eigenstate. In this paper, based on several selected pulsed NMR experiments, we develop and extend the simple vector model to deal with more complicated multipulse situations. We show that the vector model not only provides a good simple physical insight into these selected problems but is also a rigorous description of the quantum-mechanical evolution. As such, it will prove a viable and useful simple alternative to the density matrix approach for the understanding and design of new specific pulse sequences.

Polarization transfer pulse sequences for two-dimensional NMR by heisenberg vector analysis

Abstract There are 24 possible polarization transfer pulse sequences having two or three precessional periods in which the effects of heteronuclear coupling and chemical shift are separated by refocusing pulses. Six of the most useful of these pulse sequences are described in detail using the Heisenberg vector approach. The vector description enables a clear analysis of the outcome of each sequence and of the modifications which are necessary to optimize each sequence. Each sequence is analyzed for the production of artifacts and a simple general method for the phase correction of the two-dimensional spectra is described.

Two-dimensional 13C1H polarization transfer J spectroscopy

Abstract Modification of the INEPT sequence enables application of the sequence to two-dimensional NMR and provides a simplified form of two-dimensional 13 C J spectroscopy. The problem of phase correcting the final spectrum has been solved and the source of artifact signals has been identified and the problem alleviated. The uses and advantages of this form of two-dimensional spectroscopy are briefly described.