We examined the association between alterations in regional neural activity and topological measures of inter-regional FC and their interactions in HC, MCI, and AD. Our findings demonstrated the following points: i) cortical hypometabolism along with reduced CC/DC in various brain regions (Fig. 1, 2); ii) congruent alterations in rFDG and FC topology in form of reduced rFDG and reduced CC/DC in the bilateral inferior temporal gyri and left superior temporal gyrus, left superior parietal lobule, left angular gyrus and left lateral occipital gyrus (Fig. 3); iii) incongruent alterations in form of increased rFDG associated with reduced CC/DC in the right temporal occipital fusiform and bilateral precentral cortices (Fig. 3); iv) a significant two-way interaction between rFDG and “clinical diagnosis as AD” predicted alterations in CC of the right ITG among the overlapping regions (Fig. 4A); v) a significant two-way interaction between rFDG and “clinical diagnosis i.e., AD” predicted CC alterations in the right SMA and DC alterations in the right planum temporale among the non-overlapping regions (Figs. 4B, 4C); and vi) a significant two-way interaction between inter-regional FC metrics and “clinical diagnosis i.e., AD” predicted rFDG alterations in the left middle temporal, supramarginal, and parahippocampal, among the non-overlapping regions in the control analysis (SI-Figures 2, 3). These findings suggest that AD disrupts a coupling between rFDG and FC topology in the right inferior temporal and supplementary motor area, as well as the left middle temporal, supramarginal, and parahippocampal regions.
4.1. Hypometabolism and disrupted inter-regional FC topology in MCI/AD
Hypometabolism and FC disruption, mainly in the posterior part of DMN, are well-documented features of AD that are suggested to be strongly linked with grey matter atrophy, amyloid beta deposition and tau accumulation [3, 18, 31]. We also observed relative hypermetabolism in MCI and AD in the bilateral precentral and lingual gyri, in line with previous studies [6, 32, 33]. Moreover, changes in the topology of the functional connectivity networks of several cortical areas within and outside the DMN have been reported in MCI and AD . Neurobiological mechanisms of the link between regional changes of metabolism and disruption of functional network topology is yet to be investigated. Of note, it has been suggested that functional decoupling between the temporal lobe and posteromedial cortex, as the main hubs of DMN, contributes to disinhibition-like changes in the hippocampus and induce hyperexcitability in the medial temporal lobe . This pathological hypermetabolism in the medial temporal lobe might precipitates the age-associated tau deposition in this region, leading to a loss of white matter integrity and structural dysconnectivity between the temporal lobe and posteromedial cortex .
4.2 The effect of “clinical diagnosis as AD” on the reginal neural activity and inter-regional FC topology link
We revealed that AD altered the coupling between rFDG and inter-regional FC topology matrices. In particular, AD interacts with rFDG to predict regional CC of the right ITG and right SMA and to predict DC in the right planum temporale. Aberrant coupling between rFDG and FC topology metrics in patients with AD indicates that AD might affects the rFDG-CC and rFDG-DC links. The altered association between rFDG and FC in AD has been well-documented previously. For example, A longitudinal study demonstrated that severity of amyloid deposition in the regions with high degree of amyloid beta pathology (i.e., in the posterior DMN) can predict progressive hypometabolism in remote, but functionally connected areas, with minimal amyloid pathology . In another study, rFDG/FC decoupling was found in several areas within the posterior DMN , followed by another study demonstrating that the rFDG/FC decoupling in the posterior DMN is directly correlated with amyloid beta deposition . In this study, Scherr and colleagues found that rFDG progressively decoupled from FC in the posterior DMN and degree of this decoupling associated with amyloid beta load . The authors identified "rFDG-FC coupling" as the only significant variable, which predicted cognitive status of the patients with early and late MCI and AD. Our results support their findings by showing the adverse effects of AD on coupling between rFDG and topological metrics of inter-regional FC. Similar to this study , we found widespread and congruent alterations in rFDG and FC topology in the main hubs of DMN, including the parahippocampal gyrus, and the middle and inferior temporal gyri, suggesting that AD pathology in the DMN can be (at least partly) accountable for the changes observed in our study. It is worthy to mention that amyloid beta and tau pathology interact in their regulation of synaptic function. Synaptic tau and amyloid deposition mutually precipitate signaling pathways that culminate in progressive synaptic dysfunction and loss [37, 38]. Indeed, it has been demonstrated that in individuals with normal amyloid-beta level, FC has an inverse correlation with the degree of tau deposition . A similar model demonstrated that cascading network failure is mediated by amyloid deposition in the DMN along with global tau deposition . Based on these findings and a recently proposed model by our group , it seems that amyloid beta and tau pathology might be important driving forces for alterations in rFDG, FC topology, and rFDG/FC decoupling in AD, which should be directly tested in future.
The role of ITG in AD has been assessed and it’s hypometabolism, despite minimal amyloid beta deposition is reported earlier . Interestingly, hypometabolism in the ITG is linked with conversion from MCI to AD, which is known to be associated with increased whole brain amyloid burden [42, 43]. Similarly, higher activity in the ITG predicts better cognitive reserve in AD patients [44, 45]. Importantly, amyloid beta deposition in the parieto-temporal cortices is associated with longitudinal tau deposition in the ITG in early AD , suggesting that tau pathology might be an important contributor to rFDG/CC decoupling in the ITG. In addition, we identified that interaction between changes in rFDG and clinical diagnosis predicted the DC alterations in the planum temporale. The planum temporale is an important subcomponent of the superior temporal gyrus and auditory cortices and is highly asymmetric between left and right hemispheres primarily as a reflection of language lateralization , but also as a result of handedness . This asymmetry in cortical thickness and morphology becomes more pronounced in AD, as evidenced by post-mortem findings of altered pyramidal cortex morphology in this region . Finally, increased amyloid burden in post-mortem brains of AD patients in this region have been shown to be associated with cognitive decline .
Although intact glucose metabolism in the primary motor cortex (M1) and SMA has been considered as a distinguishing feature of AD from other dementias [51, 52], it has been suggested that hypermetabolism in some cortical regions occurring in the early stage of disease may represent a compensatory response to the neural damage . Here, we found relative hypermetabolism in the SMA and precentral gyrus in AD, which is in line with increased FC between the SMA and M1 cortex with the sensorimotor, cingulate, and fusiform cortices both in MCI and AD patients [53, 54]. As amyloid and tau accumulation in the M1 and SMA has do not occur until late stages of AD [55–57], we speculate that the observed SMA relative hypermetabolism could be a compensatory phenomenon, rather than a result of direct AD pathology. Nonetheless, as regional brain FDG uptakes are normalized for global brain metabolism in our study, this observation might be a relative phenomenon. Put differently, as glucose uptake reduces in several brain regions, areas like the motor cortices with preserved metabolism appear to show a higher rFDG. Conversely, we observed reduced both CC and DC in the precentral gyrus and SMA in MCI and AD, indicating lower local and global information processing in the functional connectome of the SMA. Beside the motor areas, we observed rFDG and FC topology alterations in the lateral occipital cortex and occipital fusiform gyrus, which play a key role in visuospatial disturbance in patients with AD [58, 59] (SI-Tables 1, 2 and 3). We assume that tau pathology might be responsible for rFDG and topology alterations beyond the DMN. This is perhaps supported by the fact that tau deposition might be more strongly associated with rFDG decline, than amyloid deposition . Moreover, connectivity analysis based on tau imaging showed moderate spatial overlap, not only within the DMN, but also in the visual and language networks .
In addition, we investigated another hypothesis considering CC/DC and clinical diagnosis as the predictive factors and investigated whether their interaction could predict rFDG aletrations. This analysis revealed a significant interaction between clinical diagnosis as AD and CC/DC in left supramarginal, left middle temporal gyri, and left posterior parahippocampal gyrus, which are part of the medial temporal lobe and further highlights the role of DMN in pathophysiology of AD. In line with our findings, the supramarginal gyrus has shown reduced inter-regional FC, as well as loss of long-range FC with the central executive and frontoparietal network in AD . While regional hypometabolism in the supramarginal gyrus is shown to have a low discriminative value for AD  and changes in rFDG where not shown to be significant between AD and HCs in our study, the interaction between clinical diagnosis as AD and rFDG was able to predict changes in CC of the supramarginal gyrus. The parahippocampal gyrus is also part of the medial temporal lobe, which has shown in inverse U pattern of change in local metabolism along AD trajectory . It has been hypothesized that amyloid beta accumulation in the posteromedial cortex disrupts its long-range FC with the medical temporal lobe, which in turns gives rise to disinhibition and increased local metabolism in the medical temporal lobe including the parahippocampal gyrus. These changes enhance regional amyloid and tau deposition in the temporal lobe, further FC disruption to the remote areas, and finally widespread atrophy. Our findings are in line with this hypothesis, as we observed that AD interacts with loss of DC to predict regional relative hypermetabolism in medical temporal lobe regions including the parahippocampal gyrus .