Introduction
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that results in progressive loss of cognitive function. AD is characterized by the accumulation of the amyloid-beta (Aβ) peptide into amyloid plaques in the extracellular brain parenchyma and by intraneuronal neurofibrillary tangles caused by the abnormal phosphorylation of the tau protein [
1]. Amyloid deposits and tangles are necessary for the post mortem diagnosis of AD [
2].
Imaging techniques, such as positron emission tomography (PET), have long been used to visualize brain damage in AD and in mild cognitive impairment (MCI), often a prodrome to AD [
3]. There is increasing evidence that reductions in the cerebral metabolic rate of glucose (MRglc), as measured with PET using [18F]-fluoro-2-deoxyglucose (FDG) as the tracer, can be consistently detected in MCI patients compared to age-matched normal controls, mostly involving the parieto-temporal, posterior cingulate, and medial temporal cortices [
4‐
7]. MRglc is an index of synaptic functioning and density [
8], but hypometabolism is not specific to AD, as it is observed in other neurodegenerative disorders (see [
9] for review). Moreover, MCI is a clinical diagnosis in need of confirmatory biological evidence for disease. A recent large population-based study showed up to 40% of patients with MCI who were subsequently diagnosed as cognitively normal [
10].
The PET tracer,
N-methyl[11C]2- (4'-methylaminophenyl)-6-hydroxy-benzothiazole, better known as Pittsburgh Compound-B (PIB), was used to detect amyloid deposition in vivo. Prior PIB-PET studies demonstrate quantitative increases in PIB uptake, reflecting greater amyloid burden, in AD and MCI patients compared to controls [
11‐
14]. In AD, PIB uptake is particularly evident in the frontal, parieto-temporal, and posterior cingulate cortices, in keeping with the known distribution of amyloid plaques [
15‐
17]. However, recent data also show that many MCI patients fall in between AD and control values for PIB binding, and some clinically normal subjects also show an elevated PIB uptake [
13,
14]. These findings are also consistent with clinico-pathology studies showing that typical amyloid lesions are found in both demented and non-demented individuals [
18,
19]. These results suggest that the presence of amyloid may be necessary, though not sufficient for the symptoms consistent with the MCI stage of AD. The present study used a newly developed automated region of interest technique to compare the diagnostic value and concordance of FDG-PET and PIB-PET in AD and MCI.
Statistical analysis
The general linear model (GLM) univariate analysis of variance (ANOVA), with Tukey post hoc tests, was used to examine demographic, clinical, FDG MRglc, and PIB uptake measures across the three clinical groups. All significant results were confirmed using the nonparametric Mann–Whitney test with Bonferroni correction for multiple comparisons. Categorical demographic variables were examined with Chi-Square analysis and confirmed with Fisher’s exact tests. PIB DVR is expressed as a ratio to cerebellar uptake. MRglc measures were adjusted for cerebellar MRglc as a covariate in the GLM. The bilateral regions showing the largest group effects (as determined by MANOVA) were examined with logistic regressions and ROC curves to assess their diagnostic accuracy in classifying the NL, MCI, and AD groups. The ROC curve was also used to determine optimal cutoff value for MRglc and PIB DVR in separating NL, MCI, and AD. Results were considered significant at p < 0.05. All analyses were done using SPSS 12.0 (SPSS, Chicago, IL 2004, USA).
Discussion
The uptake of the beta amyloid PET tracer [11C]PIB was significantly increased in AD compared to age-matched healthy controls. This effect was found bilaterally in the middle frontal gyrus, anterior putamen, inferior parietal lobule, and the posterior cingulate cortex. In MCI, a lesser pattern of PIB uptake was found involving the middle frontal gyrus and inferior parietal lobule. This observation is also consistent with findings reported in previous studies [
14,
34]. The FDG-PET data demonstrated that AD patients show a pattern of bilateral MRglc reductions in the hippocampus, posterior cingulate, inferior parietal, and frontal cortices, while MCI patients presented with hypometabolism most consistently in the hippocampus and in the parietal cortex. These findings are also consistent with prior FDG-PET studies [
6,
7,
37,
38,
39,
40].
The MFG PIB uptake separated 16 out of 17 AD patients from NL control with 100% specificity and 96% sensitivity. This contributes to the view that [11C]PIB-PET will have utility as a diagnostic marker for AD. Only one 73-year-old male AD patient [Global Deterioration Scale (GDS) 5, MMSE 19] showed low PIB retention (DVR = 1.29). The finding of occasional “PIB negative” AD patients has been previously reported [
14,
35], and the reason is unclear. Such findings require post mortem clarification. On the other hand, the FDG-PET scan of this AD patient showed evidence for a neurodegenerative disorder consistent with AD, as reflected in the bilateral MRglc reductions in the parieto-temporal posterior cingulate cortices and medial temporal lobes. While direct diagnostic comparison between PIB and FDG imaging is uncommon, a previous study [
36] reported PIB-PET to be superior to FDG-PET in classifying AD from NL. Unlike our study, this paper only studied neocortical regions and not hippocampus, which we found most discriminative on FDG-PET. Our study shows that the best regions for FDG-PET (hippocampus) and PIB-PET (middle frontal gyrus) have high diagnostic agreement for AD (94%) and NL (86%) indicating approximately equal value in the clinical diagnosis of AD. The combination of two PET modalities did not improve the diagnostic discrimination between AD and NL. That there was no appreciable increase in the classifications of AD and NL, is attributable to the very high accuracy each modality achieved on its own.
We found that several PIB regions were found to discriminate between MCI and NL with accuracies in the 60–75% range compared with FDG regions that performed in the 70–85% range. FDG-PET appears to be superior to PIB-PET in the classification of NL and MCI. Moreover, the diagnostic agreement between the two PET modalities for MCI was only 54%; four MCI subjects with MRglc reductions showed low PIB retention and one MCI subject with normal MRglc showed high PIB retention. With MCI subjects separated into high PIB uptake (AD-like) and low PIB uptake (NL-like) groups (Fig.
5), we found that the MCI subjects with high MMSE scores (≧28) have NL-like PIB scans and MCI subjects with low MMSE scores have AD-like PIB scans. Moreover, elevated PIB and low MRglc was found in 100% of low performing MCI compared with only 33% agreement for the high performing MCI. These data suggest that low performing MCI subjects with PIB positive scans are at increased risk for dementia. Overall, the data show that the combination of two PET modalities improves the diagnostic discrimination between MCI and NL. Longitudinal studies are needed to clarify the utility of the PIB and FDG-PET imaging in assessing risk for AD.
Our results comparing MCI and AD showed different patterns of regional involvement depending on the PET imaging modality. We observed that the mean PIB values for several regions differed between MCI and AD and that their diagnostic classifications were significant. Consistent diagnostic PIB effects (~70% accuracy) were found in the middle frontal gyrus, posterior cingulate, inferior parietal lobule, and the superior temporal gyrus. For FDG, the hippocampus, the only region that showed a mean MRglc reduction in AD relative to MCI also showed the only significant diagnostic effects (~80%). This result of modality-specific informative regions underlies our second example where the combination of the two PET techniques yields complementary information in the detection of pathology. In our study, the combination of the two PET modalities improved the diagnostic discrimination between MCI and AD and between MCI and NL.
We did not observe an inverse relationship between the regional PIB and FDG data in AD as reported by others [
14,
35]. This discrepancy may be in part due to the statistical designs used to study the data. Klunk et al demonstrated a significant correlation in the inferior parietal cortex in a combined group of AD and NL patients. However, they observed that this effect did not remain significant when only AD patients were studied. [
14]. While Edison et al. showed lower CMRglc values correlated with higher PIB uptake ratios in temporal (
p = .05,
r = −0.58) and parietal lobes (
p = .041,
r = −0.60) in 12 AD subjects, they also observed a high frontal amyloid load in the face of spared glucose metabolism. These preliminary results suggest that the weak inverse correlations observed may be due to either group diagnostic effects or to different regional metabolic vulnerability due to the complex neuropathology of AD. Overall, it appears that amyloid plaques may not be directly responsible for neuronal dysfunction in AD.
In the present study, we describe the continued development of an automated ROI technique custom-tailored for FDG and PIB-PET images (see
Appendix for technical details). Several automated tools are used in neuroimaging studies to examine and sample brain regions. Foremost, voxel-based analysis (VBA) techniques with statistical parametric mapping procedures provide examination of statistical effects through the whole-brain on a voxel-by-voxel basis [
41,
42]. The basic procedure in VBA involves the spatial normalization and smoothing of each individual PET scan to a spatially standardized brain reference image (i.e., the “template” image) in the stereotactic space, thus enabling automated voxel-by-voxel assessment of statistical effects [
41,
42]. However, the MRI-guided ROI technique remains the gold standard for PET sampling, especially in aging and degenerative diseases, because of its superior anatomical precision. On the other hand, the conventional manual ROI sampling is time consuming and operator dependent, and PET images are often acquired without a corresponding 3D research MRI. To examine large data sets with reasonable anatomical precision, we describe the development of an automated ROI technique custom-tailored for sampling the cortical and medial temporal lobe regions affected in AD on FDG and PIB-PET images. These procedures were validated against the gold-standard manual ROI determined on the co-registered MRI scans. The automated ROI data in this project showed high anatomical precision as assessed on the MRI scans and high agreement with respect to the manual MRglc sampling (
r’s > 0.90) and manual PIB sampling (
r’s > 0.90; detail was described in
Appendix). In the present study, the anatomical accuracy of the automated ROIs was excellent in all subjects, and positional adjustments were not made.
Our automated method offers several advantages compared to other commonly used image analysis tools. First, the ROIs are applied via inverse transformation to the original image instead of the spatially normalized image, thus preserving the anatomical shape of the region and avoiding possible sampling errors. Moreover, the anatomical precision of the ROIs can be directly examined on the MRI and PET scans in the original space, and manual adjustments can be made if necessary. Furthermore, we applied a sampling strategy to optimize gray matter sampling, which minimizes partial volume effects and nonspecific white matter binding, which may confound detection of regional changes on PIB-PET.
There are some limitations in this study. First, the recruitment of patients at a university-based unit limits the generalization of the results. Second, we used a probabilistic gray matter sampling technique instead of the traditional MRI-based atrophy correction. While our tests suggest comparability between the two techniques, there remains the possibility that it may not remove partial volume effect thoroughly. Third, this study relied on cross-sectional data where longitudinal follow-up studies are needed to determine the predictive accuracy of PIB-PET and FDG-PET in the MCI progression to AD.