This FDG-PET study tracked the progression of CMRglc abnormalities during the decline from normal cognition to the onset of clinical symptoms of MCI and DAT, with postmortem verification of diagnosis. Longitudinal FDG-PET examinations in this cohort demonstrated that CMRglc reductions precede the onset of clinical symptoms by many years and correlate with dementia severity in life and pathological diagnosis of AD. Furthermore, the present results offer temporal and topographical in vivo information on the progressive involvement of different brain regions in the development of AD. Although FDG-PET profiles somewhat varied across subjects, CMRglc reductions were consistently detected in the HIP (Supplementary File 2
), followed by the parietotemporal and PCC cortices at the MCI or mild dementia stages. HIP CMRglc reductions appeared to precede those in the cortical regions in cognitively normal individuals declining to DAT, while the cortical hypometabolism became evident by the time of the expression of symptoms.
The regional progression of the CMRglc abnormalities foreshadowing the onset of AD had not been clearly defined because of the lack of longitudinal FDG-PET studies with post-mortem verification. Previous FDG-PET studies that explored the preclinical stages of AD relied on the clinical diagnosis as the gold standard against which imaging measurements were compared because of the lack of post-mortem data. The few PET studies that followed cognitively normal individuals over time showed that CMRglc reductions in the hippocampal formation predict future cognitive decline and are longitudinally associated with the progression to MCI and late-onset AD in sporadic cases [9
]. These studies also provided evidence for a progression of CMRglc reductions originating in the HIP and extending to the PCC and temporal cortices prior to the involvement of other neocortical regions during the decline from normal cognition to DAT [10
The present FDG-PET findings substantiate prior longitudinal observations without post-mortem examinations by showing a progression of CMRglc deficits from the HIP to the association cortices in pathologically confirmed normal individuals who developed MCI and DAT, and in patients with mild DAT who further deteriorated over time. These in vivo imaging findings are consistent with the idea of progressive pathological spreading in AD from the hippocampal formation to the association cortex [8
] and with the Braak and Braak staging model of NFT pathology in AD [18
]. Studies have shown that the progression of NFT in the brain can be staged and that the pathological changes develop many years before the clinical manifestations of the disease become apparent using standard approaches to assessment [18
]. The pattern of hypometabolism seen in the progression of individuals from normal aging to AD is consistent with Braak stages of NFT pathology determined at autopsy. Moreover, CMRglc in AD-related regions correlated with Braak stages of NFTs and with dementia severity in life.
Our findings are in agreement with previous observations of a relationship between CMRglc and CBF reductions in AD and regional densities of NFTs [31
]. These cross-sectional findings did not provide direct evidence for longitudinal progression of brain abnormalities, which could only be inferred from contrasting groups of individuals at different stages of NFT pathology. Our longitudinal FDG-PET studies allowed direct examination of the temporal and topographical progression of disease.
Our findings showed a good correspondence between FDG-PET findings in life and histopathological diagnosis. The two patients who declined from NL to DAT and received a post-mortem diagnosis of definite AD (patients 3 and 4) already showed a clear FDG-PET pattern of hypometabolism in the parietotemporal, PCC and medial temporal cortices at the MCI stage. On the other hand, the two patients who declined from NL to MCI but did not progress to DAT or show definite post-mortem evidence of AD pathology (patients 1 and 2) did not present with FDGPET evidence for AD in life. For example, patient 2 presented with apathy and forgetfulness at the first examination, and developed memory deficits and motor difficulties at follow-up. This patient showed mild CMRglc reductions in life, involving the HIP and cingulate cortices, and LBD pathology at death with AD-related features, mainly NFT in the limbic lobes (Braak stage III). These data suggest that the patient's symptoms in life may have been related to an interaction between different disease processes, with NFT pathology possibly accounting for hypometabolism in memory-related regions and amnestic symptoms, and LBD pathology for the motor symptoms.
FDG-PET examinations also appeared to be of value in detecting pathological features that were not clinically evident. For example, patient 5 retained a clinical diagnosis of DAT throughout the study period and showed pathological features of AD and additionally diffuse LBD. The FDG-PET scan showed parietotemporal with additional occipital hypometabolism, which is a well-established feature of LBD [28
]. FDG-PET in this patient reflected the presence of LBD pathology that was not detectable on clinical examination. Additionally, frontal hypometabolism was evident on the baseline PET but not at follow-up, suggesting that the frontal deficits in this patient were due to a reversible functional abnormality, whereas the HIP, PCC, parietotemporal and occipital hypometabolism was due to AD and LBD pathology.
In the largest FDG-PET series of patients with pathologically verified dementia available to date, the presence of CMRglc abnormalities on ante-mortem FDG-PET scan correctly predicted post-mortem AD diagnosis with 88% accuracy, including patients with mild dementia [33
]. Our data indicate that CMRglc reductions consistent with AD can be detected prior to the onset of dementia and progress with dementia severity, suggesting that FDG-PET imaging has the potential for contributing to clinical diagnosis at the preclinical AD stages.
The present results are based on a limited number of patients and caution is required in the interpretation of the results, which need to be replicated with larger samples in order to test their generalizability to the population. Due to the small number of subjects, our analysis was based on the comparison of each PET scan to a database of healthy controls [25
]. In view of using FDG-PET to develop preventive measures for AD, absolute quantitation of CMRglc is necessary. Additionally, we used two voxel-based analysis techniques, one that highlights hypometabolism in the form of 3D-SSP maps [23
], and the other that enables quantification of CMRglc within specific ROIs [10
]. We previously showed that whole-brain voxel-based analysis does not provide accurate quantification of CMRglc within small brain regions, such as the HIP, in AD [26
]. Accordingly, in this study hippocampal hypometabolism was not consistently detectable on the 3D-SSP images of the medial brain views, whereas it was significant using the anatomically precise ROI approach.
Our correlation analysis was based on descriptive statistics. We used a semiquantitative approach to characterize pathological lesions post mortem, and correlated Braak stages of NFT (range 0-6) with CMRglc. We could not examine correlations between amyloid load estimated using CERAD scores (i.e., possible or definite) and CMRglc, as five of the seven subjects were judged to have `definite' AD (). Quantitative histological studies are needed to directly examine the relationship between CMRglc, amyloid and NFT load. Lastly, we did not perform partial volume correction of the FDG-PET data because different MRI scanners were used throughout the years. Partial volume correction using MRI with different resolutions may hinder detection of longitudinal CMRglc changes. However, we have previously demonstrated that longitudinal CMRglc reductions observed in NL decliners to MCI/AD as compared to stable NL remain significant after partial volume correction, and therefore represent true reductions in CMRglc per gram of brain tissue [9