See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

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