124 Chapter 5 AD (as shown by the result of the current study and by others (e.g.[7, 51, 53])), and is an important hub in higher-order cognitive networks[58]. If networks like these, or their cross-network relationships, segregate with older age[59-61] it might be that the relative importance of the regions affected by either tau pathology or decreases in rCBF decrease with older age. This would be reflected by a weakened association between tau pathology or rCBF and cognition (executive functioning specifically) in late- compared to early-onset AD. In the current study we used R1 images as a measure of cerebral blood flow. This measure is tightly linked to hypometabolism measured with FDG-PET[19, 24], and others have shown decreased occipito-parietal glucose metabolism in early-onset AD[7, 62]. In contrast, our regional analyses did not show lower rCBF in early- vs late-onset AD. However, additional voxel-wise comparisons showed more fine grained decreased rCBF in lateral parietal and occipital regions in early-onset AD. One explanation for these findings might be that there are no extensive or clear differential patterns of cortical reductions in rCBF in early- vs late-onset AD, or that differential reductions in rCBF may be restricted to specific cortical gyri. Another explanation could be that R1, which is a proxy of rCBF, is not sensitive enough to capture the differences between early- and late-onset AD. As rCBF decreases with age[63], this might suggest that early-onset AD patients are more severely affected by deficits in rCBF compared to late-onset AD patients, which in turn might be caused (in part) by the higher levels of tau pathology present. Ideally one would investigate whether early-onset AD patients are indeed more heavily affected by reduced rCBF by including age-matched control groups, but since we had no such data available, it remains to be elucidated in future research. Our results showed that early-onset AD patients exhibit higher levels of tau pathology in widespread neocortical regions compared to late-onset AD patients, but no differences were found in the medial temporal lobe. Others found higher levels of tau pathology primarily in (pre)frontal and (inferior) parietal cortices in early- relative to late-onset AD, and no differences in the medial temporal cortex[53]. Another study similarly showed that early-onset AD patients, showed greater binding in the inferior parietal, occipital, and inferior temporal cortices[64]. The pattern of cortical involvement as found in the current study thus are highly consistent with previous findings, indicating that the development of high levels of tau pathology follows a specific spatial pattern within early-onset AD patients. Supporting this, a recent study identified four distinct spatiotemporal trajectories of tau pathology in AD, each presenting with distinct demographic and cognitive profiles and differing longitudinal outcomes. The medial temporal lobe-sparing subtype for example, was associated with younger age, less APOE4 allele carriership, and greater overall tau burden[65], which is largely in accordance with findings in our early-onset AD
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