Cognitive performance was significantly correlated with [18F]FDDNP signal in right frontal and parietal regions in cognitively intact subjects, suggesting that some cognitive aging that is considered age-normal actually may reflect pathological brain changes, particularly in subjects at risk for AD. That is not to say that plaque and tangle accumulations are a result of aging or are present in all older adults, but rather that in some people diagnosed as having normal cognitive aging, plaques and tangles may be associated with their subtle cognitive decline. Both the lack of significant positive correlations between [18F]FDDNP signal and composite cognitive scores and the rigor of permutation testing supported the validity of our findings.
It is important to note that even though [18F]FDDNP signal was elevated in the medial temporal lobe in some cognitively intact adults, it was primarily in the frontal cortex where [18F]FDDNP signal distinguished those controls who performed better on certain cognitive tasks from those who performed worse. Permutation testing without a restricted a priori search region appropriately applies a somewhat conservative correction for false positives, so the correlation in the right hemisphere but not the left may reflect limited statistical power rather than true hemispheric specificity. The specificity of the relationship between [18F]FDDNP signal and cognition for right frontal cortex will be tested specifically in future studies having larger sample sizes.
The correlations we observed in the cognitively intact subjects alone were maintained and expanded when cognitively impaired subjects were also included in the sample. Cognitive performance across all subjects was correlated with [18
F]FDDNP signal in inferior and lateral temporal, orbitofrontal, dorsolateral prefrontal, and parietal association cortices—regions with the greatest plaque and tangle burden in histopathological studies of AD (Braak and Braak, 1991
). The anatomical agreement is striking between these in vivo
maps and the well-established post mortem
maps for the staging of AD (Braak and Braak, 1991
ROI analyses yielded significant relationships between the composite cognitive scores and the average [18F]FDDNP signal in all regions examined when all subjects were included, but only in the posterior cingulate gyrus when cognitively intact subjects alone were considered. Given the reduced sample size and the restricted range of variability in the [18F]FDDNP signal within the control group, it is not surprising that the controls alone did not demonstrate significant relationships between [18F]FDDNP signal and the composite cognitive score in several of the ROIs. When there is a restricted range of variability in the [18F]FDDNP signal (as there is within the control group), a voxel-wise approach may provide advantages over an ROI approach (in which signal is averaged across significant and non-significant voxels) for detecting relationships between [18F]FDDNP signal and cognition. It is interesting to note, however, that even using these averaged ROIs to determine [18F]FDDNP signal, the graphs in demonstrate that there do not appear to be outlying data points in the relationships between [18F]FDDNP signal and composite cognitive scores within the controls, lending support to the significant relationships we found using a voxel-wise statistical mapping approach.
The relationship of plaques and tangles to AD is controversial. Both must accompany specific cognitive impairment for a definitive AD diagnosis (McKhann et al., 1984
). Some researchers believe that plaques or tangles cause the disease (Binder et al., 2005
; Selkoe, 2001
); others contend that these merely tend to co-occur with other more causative disease processes (Castellani et al., 2006
; Watson et al., 2005
). Neurofibrillary tangle density correlates more strongly with disease severity and neuronal death than does total plaque burden (Berg et al., 1998
; Giannakopoulos et al., 2003
). However, even in studies in which total plaque load did not correlate with disease severity, a simple comparison of total plaque load in AD subjects versus controls (rather than a correlation with severity of dementia) showed that AD subjects had on average more extensive plaques than controls (Bouras et al., 1994
; Gomez-Isla et al., 1996
). These data suggest that both plaques and tangles are good indicators of disease processes, regardless of whether they are causative factors in AD. Although we are unable to distinguish [18
F]FDDNP signal associated with amyloid plaques from that associated with tau neurofibrillary tangles in vivo
, a recent study compared [18
F]FDDNP-PET scanning and brain autopsy assessment in the same patient (Small et al., 2006
). In that study, [18
F]FDDNP signal in the medial temporal lobe was mainly associated with tau pathology whereas that in other areas of the brain was overwhelmingly related to amyloid plaque deposition.
We did not find a significant correlation between cortical thickness and either [18
F]FDDNP signal or cognition in the current study. However, the significant correlations between [18
F]FDDNP signal distribution and cognitive ability in the current study were evident in the same regions that showed cortical thinning related to more advanced AD in our prior studies () (Thompson et al., 2003
). As such, the pattern of cortical [18
F]FDDNP signal in this cognitively intact and mildly affected population very closely matches the topography of cortical thinning known to appear later, albeit with a substantial time-lag. Previous studies that considered cognition and cortical thickness either focused primarily on cognitively impaired subjects or had larger subject samples than we had in the current study (Apostolova et al., 2006
; Lerch et al., 2005
; Thompson et al., 2004
). In contrast, nearly half of the subjects in the current study were normal controls who would not be expected to show anything more than the most subtle pathology-related cortical thinning. This early distribution of plaques and tangles may therefore be followed by MRI-detectable cortical thinning only when neuronal damage has become more extensive than is typically found in cognitively intact older adults. Our results suggest that plaque and tangle deposition occurs early and precedes detectable changes in cortical structure, so [18
F]FDDNP may be more sensitive to early cognitive changes than structural MRI measures are, and therefore may offer greater power for disease detection, at least during the early stages of the disease process.
Without partial volume correction, PET measures are influenced by cortical atrophy, which reduces the gray matter volume emitting radioisotope signals, resulting in signal attenuation. However, partial volume correction is arguably less critical for interpretation of [18F]FDDNP-PET scans than for metabolic or perfusion PET images, as the disease tends to elevate [18F]FDDNP signal and reduce cortical thickness. Therefore, any atrophic effect works against finding a disease-associated PET signal increase, and PET increases cannot reasonably be attributed to cortical thinning; use of uncorrected values is, therefore, a slightly conservative approach. It also avoids the risk of overcorrecting the signal values, which could occur if the partial volume model was not exactly correct, and ensures that any observed [18F]FDDNP signal increase can be interpreted as related to the ligand and not to structural atrophy. Future empirical estimation of partial volume models for different gray/white matter fractions and local cortical geometries may increase the signal-to-noise ratio for detecting correlations with cognition with this ligand, so the current approach should be considered as deliberately conservative.
Eighteen of our 23 subjects were APOE4+, had a known family history of dementia, or both. Because our subjects were at high risk for AD and were highly educated, those who had lower memory ability on certain tasks than their same-age peers were more likely than the general population to be affected by a pathological condition. Including participants from backgrounds representative of the general population in future studies may help to further elucidate these relationships. Finally, the results presented here are cross-sectional; longitudinal follow-up is needed to determine which control subjects will eventually develop AD.
Conflicts of interest
The University of California, Los Angeles, owns a U.S. Patent (6,274,119) entitled “Methods for Labeling Beta-Amyloid Plaques and Neurofibrillary Tangles,” which is licensed to Siemens. Drs. Small, Huang, Satyamurthy, and Barrio are among the inventors and each receives royalties in regard to the application of the FDDNP-PET radioligand. None of the other authors has real or perceived conflicts of interest.