Before discussing neuroimaging changes of relevance for the preclinical and MCI due to AD stages, it is helpful to begin by briefly overviewing the typical neuroimaging findings that have been observed over the past several years in patients with clinically manifest AD dementia. Numerous studies have determined that the pattern of Aβ deposits detected in the brains of living subjects diagnosed with AD dementia using [C-11]-PiB PET closely matches the pattern predicted by the histochemical detection of Aβ in postmortem brain tissue from subjects with clinical AD [8
] (). Other amyloid PET imaging tracers that have been recently developed, such as the [F-18]-labeled radioligand florbetapir (also known as [F-18]-AV-45) have shown similar results of a good correspondence between the distribution of amyloid PET and histochemically detected Aβ in the brain [11
]. Clinical utility is expected, especially from these[F-18]-labeled ligands, which possess a radiotracer half-life that is sufficiently long enough to be produced off-site and shipped to clinics. However, compared to [C-11]PiB-PET, such novel amyloid PET ligands are currently less well characterized in clinical populations of MCI and AD patients [12
The progression of amyloid deposits as assessed at different stages of AD in (A) post-mortem brain tissue using immunohistochemical techniques against Aβ and (B) in vivo amyloid-PET scans
During the pre-clinical stages of AD, the pattern of Aβ in the brain, as derived from histochemical post-mortem brain examinations [17
], shows an initial diffuse distribution within the neocortex and progresses towards the temporal allocortex, including the hippocampus, as well as subcortical brain structures during the course of the disease (). In the clinical stages of cognitive impairment, Aβ deposits are increased in both the amount and spatial extent throughout the brain [17
] (). At the stage of AD, Aβ deposits are most frequent in neocortical brain regions, hippocampus, amygdala, and subcortical brain regions (e.g. striatum and basal ganglia), but only weakly distributed within the cerebellum and some brain stem areas [17
]. . Consistent with the histochemical post-mortem findings on Aβ deposition in the brain, a distribution of amyloid PET uptake can be already seen widely within the brain in the preclinical stage [18
]. A significant increase in Aβ deposition in predilection brain areas of AD can be observed in AD dementia patients (). Based on global brain PiB-PET uptake, subjects are often dichotomized into groups with high and low PiB-PET values, i.e. PiB-PET(+) and PiB-PET(−) groups [18
]. Data from 15 research groups have shown that 96% of 341 clinically diagnosed AD patients and 24% of 651 cognitively normal elderly controls were PiB-PET(+) [18
]. This finding points out the diagnostic sensitivity of PiB-PET imaging, but also demonstrates that Aβ pathology is not specific for the dementia phase of AD, similar to what has been known from brain autopsy studies [28
Longitudinal studies including serial scans provide an assessment of individual trajectories of brain changes and give insight into variability of brain changes between different persons. A recent longitudinal study with serial PiB-PET scans has reported a mean annual increase of 4% in global PiB-PET uptake over a period of 2 years in elderly subjects with clinically diagnosed AD [29
]. However, such changes are relatively small, and show substantial variability between AD patients [30
]. Furthermore, some studies do not report a significant increase in global PiB-PET uptake with time, at least when assessed over a few years [31
], suggesting that Aβ deposition may increase only slowly or has already reached a plateau in patients with AD dementia [32
]. However, it should be noted that most longitudinal studies have so far included only small numbers of subjects (ie. usually <20 subjects), and due to the substantial variability between subjects, such studies may have lacked sufficient statistical power to detect a significant annual increase in PiB-PET [31
FDG-PET-derived measures of brain glucose metabolism and cerebral blood flow are markers of synaptic dysfunction, typically obtained during resting state (Box 1
). A characteristic pattern of hypometabolism in the temporo-parietal region of the cortex, which is involved in episodic memory function, is present at the AD dementia stage [35
]. Joint assessment of FDG-PET and PiB-PET shows the expected inverse association between both modalities within the temporoparietal region, although not frontal regions [37
], suggesting that hypometabolism in core brain regions is associated with Aβ pathology.
A well-established finding using functional MRI (fMRI; Box 1
) to examine AD-associated differences in brain activation is decreased activation in the hippocampus during episodic memory tasks [39
]. Such results are consistent with clinical findings of early episodic memory deficits in AD subjects [41
][Ref]. Abnormal fMRI-assessed brain activation can also be observed in AD subjects without engaging subjects in a cognitive task. In healthy subjects, the default network of brain regions is active during resting periods (probably a reflection of cognitive processes such as introspection) but becomes deactivated during cognitive processes that are focused on external stimulation, such as performance of a cognitive task [42
]. The intrinsic functional connectivity (i.e. the coordinated co-activation of the default network’s brain regions measured with resting state fMRI) is impaired in AD dementia subjects during the resting state as compared to cognitively healthy elderly subjects [43
]. Furthermore, the default mode network of AD subjects do not show the beneficial deactivations that healthy subjects show when assessed during memory tasks [45
].The abnormal fMRI activation and connectivity within the default model network brain regions overlaps spatially with the temporo-parietal regions of FDG-PET hypometabolism in AD subjects, suggesting that both modalities exhibit a converging pattern of functional brain impairment in AD.
Structural MRI is another imaging technique that has been used to assess brain changes in AD subjects, specifically with respect to grey matter volume changes. A recent meta-analysis that included 826 patients with AD and 1027 elderly cognitively normal subjects found that the medial temporal lobe showed the strongest changes in AD dementia [46
], with a volume loss of 20% in the hippocampus already present at a mild stage of AD dementia[46
]. Other brain areas including the lateral temporal lobe, parietal and prefrontal lobes were found to be negatively affected as well, but changes in brain regions outside of the medial temporal lobe were smaller and more variable across studies [47
An assessment of white matter fibers using the imaging technique of DTI has revealed that the fibers connecting the hippocampus and posterior cingulate gyrus are impaired in AD subjects to a significantly greater degree as compared to control subjects [43
]. This suggests that white matter damage may relate to grey matter atrophy within the temporo-parietal brain network in AD. A recent meta-analysis of DTI studies of AD subjects confirmed a large effect size of white matter damage in the posterior cingulum, but also within major white matter bundles connecting the prefrontal cortex with the medial temporal lobe or the parietal cortex [48
], suggesting that white matter damage affects large-scale networks in AD.
Taking such diverse imaging modality findings together, it is clear that gross changes in the living brain of AD dementia subjects can be visualized and measured. A hypothetical model of sequential neuroimaging changes in AD has recently been proposed [9
]and Box 2
provides an overview of disease-stage specific changes for different neuroimaging markers throughout the course of the disease. The neuroimaging changes in the early stages of disease preceding dementia are discussed in the following sections.
Box 2: Biomarkers commonly used to detect the development of AD dementia
There are a variety of neuroimaging biomarkers which are in use for the prediction and validation of AD. Some of these techniques detect core AD pathology such as amyloid deposition (as measured by amyloid PET), while other imaging modalities detect neurodegeneration such as FDG-PET and MRI assessed functional and structural changes that may occur in a specific temporal order as recently proposed [9
], Some neuroimaging detected changes occur already at the preclinical stage, others at the MCI stage and all of them are useful for detecting changes at the AD dementia stage (). The dynamic changes in neuroimaging markers are known to occur non-linearly throughout the stages of the disease [111
]. However, the exact temporal sequence of structural and functional brain changes, and how changes in these various different imaging modalities are related, remains to be determined. The model sequence model displayed presents a hypothetic framework based upon currently available neuroimaging data.
- PiB-PET imaging (orange line) – studies have observed that 10–30% of elderly cognitively normal subjects have significant Aβ deposition (ie. already at the preclinical phase) .
- fMRI-task related brain activation (red line) - Increased PiB-PET is correlated with abnormally increased hippocampus activity during memory task performance. Such functional changes begin to be observed in the late preclinical stage and decline in late stages of MCI [62, 92]. Abnormally decreased hippocampal activity is observed in these later stages [41, 45].
- fMRI assessed default Mode Network (grey line) - begins to decline in activation levels during the preclinical stage, in correlation with PiB-PET [22, 62, 113]. Resting state FDG-PET metabolism (grey line) is reduced in ApoE e4 carriers without cognitive impairment that may, however, not be accounted for by preclinical deposition of Aβ pathology .
- Volumetric MRI (green line) - MRI-detected grey matter atrophy starts primarily, though not exclusively, in the hippocampus, in inverse correlation with PiB-PET levels, and continues to decline throughout the progression of the disease [70, 112]. Widespread cortical and subcortical atrophy is observed at the dementia stage .
Box 2 Figure I
Hypothetical model of various different neuroimaging biomarkers and their predicted utility during disease progression, as based on a variety of studies discussed in this review.
Other biological-based biomarkers
Another major category of primary biomarker candidates for AD consists of CSF biomarkers (for review, see [115
]). CSF samples can be obtained from subjects by lumbar puncture and analyzed in standard laboratory tests. Major CSF-derived markers include:
- Soluble Aβ1–42, which correlates inversely with Aβ plaque deposition in the brain  and global PiB-PET scores .
- Phospho-tau, which correlates positively with neurofibrillary pathology in the brain 
- Total tau, which is thought to be associated with neuronal loss in the brain, since it is elevated in neurodegenerative diseases such as Creutzfeldt-Jakob disease, or stroke, that show large neuronal loss but are inconspicuous of AD-like neurofibrillary pathology (for reviews, see [127–128].