David M. Doddrell

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's 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.

Expressions are presented for the nuclear Overhauser enhancement (NOE), the spin-lattice relaxation time (T1), and the spin-spin relaxation time (T2) of a 13C nucleus relaxing by a dipolar interaction with one proton under conditions of complete proton decoupling, and without assuming that the extreme narrowing limit applies. Specific equations are derived for a C–H group in a rigid molecule rotating isotropically and also for a C–H group with one degree of internal motion attached to a molecule undergoing isotropic rotational reorientation. Numerical results are presented for T1, T2, and the NOE of a C–H group in a rigid molecule (undergoing purely dipolar relaxation) as a function of the rotational correlation time (τR) and the resonance frequency (ωC). T1 goes through a minimum when τRωC ≈ 0.8. The NOE varies from the expected value of 2.988 in the extreme narrowing limit to 1.153 when 1/τR is much smaller than the resonance frequency. The numerical results indicate that the signal-to-noise ratio in proton-decoupled 13C Fourier transform spectra of macromolecules in solution may not improve significantly by going to very high magnetic field strengths (such as 51.7 kG), because the increase in basic sensitivity can be offset by a decrease in the NOE and the T2/T1 ratio. The magnitude of the latter two parameters is strongly dependent on τR and the magnetic field strength. Numerical results are also presented for a C–H group with one degree of internal motion. 1/T2 is a monotonically increasing function of τR and τG (the correlation time for internal rotation). The NOE and T1 behave in a more complex manner. The onset of internal rotation may make T1 larger or smaller, depending on the value of τRωC. In the extreme narrowing limit, T1 increases monotonically as τG decreases, reaching a limiting value (when τG≫τR) of 4(1−3 cos2θ)−2T1R, where θ is the angle between the C–H vector and the axis of internal rotation and T1R is the value of T1 in the absence of internal rotation. However, for very slow over-all reorientation (with respect to the resonance frequency), the onset of internal rotation produces a decrease in T1 until it reaches a minimum and increases again. When τG→ 0, T1 reaches the same limiting value as in the extreme narrowing case. As expected, in the extreme narrowing limit for τR we get the full NOE of 2.988 regardless of the value of τG. For slow over-all reorientation, the onset of internal rotation first increases the NOE. As τG gets smaller, the NOE goes through a maximum and then decreases again. As τG→ 0, the NOE reaches an asymptotic value equal to that in the absence of internal rotation.

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 NMR signals are also demonstrated using the DEPT sequence. The only disadvantage of this pulse train compared with the INEPT sequence appears to be its greater sensitivity to spin relaxation, a consequence of its time span.