Quantitative analysis of [18F]FDDNP PET using subcortical white matter as reference region

Abstract

Purpose: Subcortical white matter is known to be relatively unaffected by amyloid deposition in Alzheimer's disease (AD). We investigated the use of subcortical white matter as a reference region to quantify [(18)F]FDDNP binding in the human brain.

Methods: Dynamic [(18)F]FDDNP PET studies were performed on 7 control subjects and 12 AD patients. Population efflux rate constants (k(')(2)) from subcortical white matter (centrum semiovale) and cerebellar cortex were derived by a simplified reference tissue modeling approach incorporating physiological constraints. Regional distribution volume ratio (DVR) estimates were derived using Logan and simplified reference tissue approaches, with either subcortical white matter or cerebellum as reference input. Discriminant analysis with cross-validation was performed to classify control subjects and AD patients.

Results: The population estimates of k(')(2) in subcortical white matter did not differ significantly between control subjects and AD patients but the variability of individual estimates of k(')(2) determined in white matter was lower than that in cerebellum. Logan DVR showed dependence on the efflux rate constant in white matter. The DVR estimates in the frontal, parietal, posterior cingulate, and temporal cortices were significantly higher in the AD group (p<0.01). Incorporating all these regional DVR estimates as predictor variables in discriminant analysis yielded accurate classification of control subjects and AD patients with high sensitivity and specificity, and the results agreed well with those using the cerebellum as the reference region.

Conclusion: Subcortical white matter can be used as a reference region for quantitative analysis of [(18)F]FDDNP with the Logan method which allows more accurate and less biased binding estimates, but a population efflux rate constant has to be determined a priori.

Figures

Fig. 1

Representative tissue TACs of a control subject (a) and an AD patient (d), and their ratios to the cerebellum (b, e) and white matter (c, f) (FRT frontal, PAR parietal, MTL medial temporal, LTL lateral temporal, PCG posterior cingulate, CBL cerebellum, SWM subcortical white matter)

Fig. 2

Correlations between estimates of relative perfusion (to the reference region) using the summed image data (Rp) within the first 6 min after injection of [18F]FDDNP, and perfusion (relative to the reference region) obtained by SRTM (R1) for various regions in control subjects and AD patients. The reference regions were white matter (a) and cerebellum (b). Regression lines are shown in gray (FRT frontal, PAR parietal, MTL medial temporal, LTL lateral temporal, PCG posterior cingulate)

Fig. 3

Logan DVR plots on the frontal cortex for a control subject (a) and an AD patient (b) using the cerebellum (CBL) and the subcortical white matter (SWM) as reference region, respectively. The value of was 0.023 min−1 when SWM was used as the reference region and it was 0.091 min−1 for the control subject and 0.086 min−1 for the AD patient when CBL was used as the reference region. Note the similarity in DVR values derived using either reference region. The time point corresponding to the “pseudo” equilibrium (t*=25 min) is also shown

Fig. 4

Logan DVR plot on the cerebellum using the subcortical white matter as reference region (a) and the subcortical white matter using the cerebellum as reference region (b) for the same subjects as shown in Fig. 3. The time point corresponding to the “pseudo” equilibrium (t*=25 min) is also shown

Fig. 5

Representative parametric images of Logan DVR using 125 min of data (with t*=35 min) and white matter as reference input in a control subject (a) and an AD patient (b)

Fig. 6

Scatter plots of regional [18F]FDDNP binding derived by the Logan method using white matter (a) and cerebellum (b) as reference regions. Long and short horizontal bars represent means and standard deviations, respectively. The p-values were calculated using a nonparametric Mann-Whitney rank-sum test (one-tailed)

Fig. 7

Effect of varying t* on the stability of regional DVR values derived by the Logan method with subcortical white matter as reference region in control subjects and AD patients for each region (n=5) and each subject (n=7 control subjects, n=12 AD patients). Percentage differences in DVR values due to increasing t* from 15 min to 85 min were calculated using estimates obtained with t*=35 min as reference values and are shown for control subjects (a) and AD patients (c), and the corresponding variability is shown for control subjects (b) and AD patients (d)

Fig. 8

Effect of total scan duration on the stability of regional DVR values derived by the Logan method with subcortical white matter as reference region in control subjects and AD patients for each region (n=5) and each subject (n=7 control subjects, n=12 AD patients). Regional DVR values derived with shorter datasets, expressed as a percentage difference from their reference values estimated with the complete datasets (125 min of data collection and t*=35 min) are shown for control subjects (a) and AD patients (c). The variability, expressed as %CV, is shown for control subjects (b) and AD patients (d)

Fig. 9

Effect of variation in in white matter on the accuracy of DVRs derived by Logan graphical analysis in control subjects (a) and AD patients (b). Variations in DVR in the frontal region (FRT), parietal region (PAR), medial temporal region (MTL), lateral temporal region (LTL), and posterior cingulate (PCG) were determined using an assumed value of 0.023 min−1