11C-PiB and 124I-Antibody PET Provide Differing Estimates of Brain Amyloid-β After Therapeutic Intervention

Visual Abstract

Al zheimer disease (AD) is a growing socioeconomic burden on society and health care in most countries that are characterized by an aging population (1). Despite intense research over the last few decades, no treatment is available that halts the underlying disease mechanisms and stops the pathologic changes in the AD brain. Accumulation of amyloid-b (Ab) plaques is the core feature of the histopathologic diagnosis of AD and can be visualized and quantified by molecular imaging. PET is today a valuable tool for assessment of brain amyloidosis in vivo. Amyloid imaging with PET has also become a regularly used inclusion criterion for enrolment of patients in clinical trials. New treatments, aiming to clear Ab from the brain parenchyma or to reduce Ab production and aggregation, are dependent on diagnostic tools to follow changes in brain Ab levels in vivo.
PET ligands such as 11 C-Pittsburgh compound B ( 11 C-PiB) and several later-developed analogs bind to fibrillar Ab, that is, the form of Ab found in insoluble amyloid plaques. However, Ab aggregation starts years before any clinical symptoms emerge, and it appears that the PET signal with amyloid radioligands such as 11 C-PiB becomes saturated rather early during disease progression (2,3). In contrast, nonfibrillar Ab oligomers and protofibrils have been reported to display a more dynamic profile during the course of the clinical stages of the disease and may therefore be better biomarkers for disease severity than amyloid plaques (3,4). Treatments aimed at reducing brain Ab, such as b-secretase (BACE-1) inhibitors, or to facilitate Ab clearance, for example, immunotherapy, are likely to reduce nonfibrillar Ab before amyloid plaques (5,6). Furthermore, diffuse Ab plaque pathology cannot be detected by these radioligands, which bind to the ordered b-sheet structures of amyloid plaques (7).
A potential strategy to image nonfibrillar Ab aggregates, rather than plaques, and thus a way to circumvent the limitations of 11 C-PiB and other amyloid radioligands could be to use an antibody-based PET approach. Antibodies are characterized by high and specific binding to their target and can be generated to show selective affinity for a specific aggregation form of Ab, for example, Ab protofibrils (8). However, antibodies display very limited passage across the blood-brain barrier and are therefore not directly suitable as radioligands that require fast and efficient brain entry. We have recently introduced several bispecific radioligands based on Ab-binding antibodies functionalized with a transferrin receptor binding component to enable active transport across the blood-brain barrier (9)(10)(11)(12)(13).
RmAb158-scFv8D3 (14) is based on the Ab protofibril selective antibody mAb158 (8,15), the murine version of lecanemab (16) that is currently being evaluated as an anti-Ab treatment in clinical phase III trials, and 2 single-chain fragments (scFvs) of the transferrin receptor antibody 8D3 (17) to enhance brain uptake. A previous study showed that PET with 124 I labeled RmAb158-scFv8D3 could be used to successfully follow Ab accumulation in mice 7-16 mo of age harboring the Arctic (Ab precursor protein [APP] E693G) and the Swedish (APP KM670/671NL) APP mutations (ArcSwe) (18). Further, 124 I-RmAb158-scFv8D3 also enabled monitoring of Ab brain levels after Ab-reducing treatment with BACE-1 inhibitor NB-360 (6,19) in a cross-sectional study design in ArcSwe mice 10 mo old, that is, an age associated with limited Ab accumulation. However, in the clinical situation, it is likely that most AD cases remain undetected until clinical symptoms such as memory impairment appear. Consequently, a disease-modifying treatment will realistically be applied at a disease stage associated with advanced brain Ab accumulation. Thus, diagnostic and dynamic biomarkers reflecting pathologic changes covering also the middle to late disease stage are required.
The aim of this study was to compare the ability of the clinically established radioligand 11 C-PiB and the novel protofibril selective radioligand 124 I-RmAb158-scFv158 to detect and quantify effects of anti-Ab intervention using the BACE-1 inhibitor NB-360 as a model drug. The study was performed on 2 different models: the first was the ArcSwe mouse model that shows 11 C-PiB positivity between the ages of 12 and 18 mo (9,20), and the second was the App NL-G-F knock-in mouse model harboring the Arctic, Swedish, and Iberian (APP I716F) mutations that is characterized by diffuse Ab pathology that is not readily detected by amyloid imaging with PET (21). By inclusion of old mice characterized by abundant brain Ab pathology, the study was designed to resemble the disease stage when patients are likely to be diagnosed and potentially enrolled into clinical trials of novel drug candidates.

Animals and Treatment
All experiments were performed according to the rules and regulations of the Swedish Animal Welfare Agency, which have been in line with the European Communities Council Directive since September 22, 2010. The experiments were approved by the Uppsala University Animal Ethics board (5.8.18-13350/2017). ArcSwe mice (22) 16 mo old were administered BACE-1 inhibitor NB-360 (Novartis) (6) nutrition pellets (0.5 g of NB-360/kg of pellets) for 2 mo. App NL-G-F mice (23), with an earlier onset of Ab deposition, were treated between the ages of 8 and 10 mo. NB-360-treated groups were compared with age-matched groups that received only vehicle food, and further, with baseline groups reflecting pathology levels at the beginning of the treatment. In total, 44 ArcSwe mice (baseline, n 5 15; NB-360, n 5 15; control, n 5 14) and 17 App NL-G-F mice (baseline, n 5 5; NB-360, n 5 6; control, n 5 6) were included in the study. Two wildtype mice 8 mo old, that is, age-matched to the App NL-G-F baseline mice, were also included as a comparison (study design is shown in Supplemental Fig. 1 and animal information in Supplemental Table 1; supplemental materials are available at http://jnm.snmjournals.org). In addition to the mice that underwent in vivo imaging, a separate group of mice, ArcSwe (n 5 2; 18 mo old) and App NL-G-F (n 5 2; 10 mo old) were used for ex vivo autoradiography. Mice had free access to food and water during the study.

11
C-PiB was synthesized using a previously described method with slight modifications related to automation using an in-house-built synthesis device (Tracer Production System) (24). The final product was reformulated using solid-phase extraction in approximately 10% ethanol in phosphate-buffered saline. 11 C-PiB was produced with a radioactivity yield of 2.1 6 1.0 GBq (range, 0.7-4.3 GBq), a molar activity of 33 6 38 MBq/nmol, and a radiochemical purity of more than 99% at the end of the synthesis.
PET/SPECT Imaging All mice underwent an 11 C-PiB PET scan. ArcSwe mice were injected with 13.2 6 3.6 MBq of 11 C-PiB with a molar activity of 19.0 6 9.3 MBq/nmol. App NL-G-F mice were injected with a 20.1 6 6.6 MBq/nmol concentration of 11 C-PiB with a molar activity of 6.7 6 1.6 MBq/nmol. Animals were either injected at the start of the PET scan and scanned for 1 h or injected 30 min before the PET scan and kept under anesthesia until the start of a 30-min scan. For all animals, 11 C-PiB brain retention was analyzed using data acquired 40-60 min after injection.
Within a week after their 11 C-PiB PET scan, ArcSwe animals were PET-scanned with 124 I-RmAb158-scFv8D3 and App NL-G-F mice were SPECT-scanned with 125 I-RmAb158-scFv8D3. One day before injection with radiolabeled RmAb158-scFv8D3, mice were given drinking water containing 0.5% NaI to reduce thyroidal uptake of 124 I and 125 I. After injection, the concentration was decreased to 0.2% NaI until the PET or SPECT scan. ArcSwe and App NL-G-F mice were injected with 11.6 6 2.7 MBq of 124 I-RmAb158-scFv8D3 and 7.2 6 1.1 MBq of 125 I-RmAb158-scFv8D3, respectively, and scanned 4 d after injection. The molar activities were 185.4 6 28.7 MBq/nmol and 144.5 6 8.8 MBq/nmol for the 124 I-and the 125 I-labeled radioligands, respectively. After PET/SPECT scanning, mice underwent transcardial perfusion with 40 mL of 0.9% NaCl for 2.5 min. The brain was then isolated and divided into right and left hemispheres, and the cerebellum was removed from the left hemisphere. Radioactivity was measured in the 3 brain samples (right hemisphere, left hemisphere without cerebellum, and cerebellum from the left hemisphere) with a Wizard 2470 g-counter (GE Healthcare). All samples were frozen on dry ice and stored at 280 C until further processing.
PET scans were performed on either a Triumph Trimodality System (TriFoil Imaging, Inc.) or a nanoScan system PET/MRI (Mediso). All PET scans performed with the Mediso system were reconstructed with a Tera-Tomo 3-dimensional algorithm (Mediso) with 4 iterations and 6 subsets. Data obtained with the Triumph system were reconstructed using 3-dimensional ordered-subsets expectation maximization with 20 iterations. SPECT scans were performed with a nanoScan SPECT/ CT system (Mediso) with 4 detectors at a frame time of 80 s. Images were reconstructed with a Tera-Tomo 3-dimensional algorithm (Mediso) with 48 iterations and 3 subsets. Each mouse was CT-examined after the PET/SPECT scan.
All subsequent processing of the images was performed with Amide, version 1.0.4 (27). CT and PET scans were manually aligned with a T2-weighted mouse brain atlas (28) to quantify activity in regions of interest (Supplemental Fig. 2).

Immunostaining and Autoradiography
Right brain hemispheres of PET-or SPECT-scanned animals were cryosectioned (20 mm) for anti-Ab1-42 chromogen staining as described previously (18) using the primary polyclonal rabbit-anti-Ab1-42 antibody (Agrisera). Triple immunofluorescence staining of Ab, ionized calcium binding adaptor molecule 1, and glial fibrillary acidic protein and autoradiography were performed as previously described (18). Images were processed as described by Gustavsson et al. (26).

Brain Sample Preparation
Brain tissue was sequentially extracted as previously described (29) according to Table 1, using a Precellys Evolution system (Bertin Corp.) (4 3 10 s at 5,500 rpm).

Biochemical Quantifications of Brain Tissue
Brain extraction samples (Table 1) were quantified with enzymelinked immunosorbent assay (ELISA) as previously described (20,30). Assay details are displayed in Table 2.

C-PiB Nuclear Track Emulsion (NTE) and Autoradiography
A separate group of mice was injected with 18-20 MBq of 11 C-PiB and then underwent transcardial perfusion at 20 or 40 min after injection. The brain was immediately removed and divided into right and left hemispheres. Brain samples were frozen on dry ice and processed into 20-mm sagittal sections for NTE and 40-mm sections for ex vivo autoradiography. Before NTE, sections were stained for 2 min with saturated thioflavin-S in 80% ethanol, washed 1 min in 70% ethanol,   and rinsed with phosphate-buffered saline. NTE was performed as previously described (29). Exposure of the slides was started 30 min after perfusion (i.e., equal to 1.5 decay half-lives of 11 C). The signal was developed after 2 h. Images were acquired with an LSM700 confocal laser scanning microscope (Zeiss) and processed with Zen Zeiss software. Images were compiled with Adobe Photoshop 2020. Brain sections from the same animals were also exposed to a phosphor imaging plate (Fujifilm) within 20 min after perfusion. Plates were exposed for 80 min and read with an Amersham Typhoon imager (GE Healthcare).

Statistics
Data were analyzed and plotted with GraphPad Prism, version 6. Groups were compared with 1-way ANOVA using the Bonferroni post hoc test. Results are reported as mean 6 SD.

RESULTS
ArcSwe and App NL-G-F mice, treated with BACE-1 inhibitor NB-360 or with vehicle, were PET-scanned with 11 C-PiB followed by a 124 I-RmAb158-scFv8D3 PET scan or a 125 I-RmAb158-scFv8D3 SPECT scan. On the basis of visual interpretation of PET images, 11 C-PiB retention in ArcSwe animals seemed slightly increased in the NB-360 and vehicle groups compared with the 2-mo-younger baseline group (Fig. 1A). When retention was quantified as SUV, a similar trend was observed in hippocampus, cortex, thalamus, and cerebellum, but the difference was not significant and interanimal variation was large (Fig. 1B). 11 C-PiB retention in App NL-G-F mice was alike in all 3 groups (Fig. 1C). When retention was quantified as SUV, interindividual variation was high and differences between the 3 groups and the wild-type group were not significant (Fig. 1D). In summary, neither of the mouse models showed a significant difference in 11 C-PiB signal between the different groups, despite a trend toward an increased signal in older mice, that is, after the 2-mo treatment period (both vehicle and NB-360), compared with baseline mice. Whole-body PET images are shown in Supplemental Figure 3. 124 I-RmAb158-scFv8D3 retention in NB-360-treated animals was clearly lower than in vehicle animals, whereas there was no notable difference from baseline animals (Fig. 1A). Radioligand concentrations were significantly lower in the thalamus (P 5 0.049) of NB-360-treated animals than in vehicle animals (Fig. 1B). The same trend was observed in cortex, hippocampus, and cerebellum but did not reach significance. Vehicle animals displayed increased levels compared with baseline (hippocampus, P 5 0.028; cortex, P 5 0.018; thalamus, P 5 0.021; cerebellum, P 5 0.039). Akin to results in ArcSwe animals, SPECT images revealed lower 125 I-RmAb158-scFv8D3 retention in App NL-G-F animals treated with NB-360 than in the vehicle group (Fig. 1C). When quantified, radioligand concentration was significantly lower in hippocampus (P 5 0.017), cortex (P 5 0.047), and cerebellum (P , 0.001) (Fig. 1D). Vehicle animals displayed increased 125 I-RmAb158-scFv8D3 concentrations in hippocampus (P 5 0.008) and thalamus (P 5 0.047) compared with baseline. 11 C-PiB binding was also assessed in postmortem brain tissue with ex vivo autoradiography and compared with Ab42 immunostaining of the adjacent brain sections ( Fig. 2A). At 40 min after injection, ArcSwe animals showed 11 C-PiB binding in regions with abundant Ab pathology such as hippocampus, cortex, and thalamus. White matter binding was observed in cerebellum, corpus callosum, pons, and medulla ( Fig. 2A). App NL-G-F mice displayed low 11 C-PiB binding in hippocampus, cortex, and thalamus despite Ab pathology but. in line with observations in ArcSwe animals, also showed distinct white matter binding. 11 C-PiB binding in the cortex was further investigated with NTE (Fig. 2B). At 20 min after 11 C-PiB injection in ArcSwe mice, the radioligand was evenly distributed in the tissue, including the core of thioflavin S-stained Ab deposits, whereas at 40 min after injection, the radioligand was localized primarily around the dense core of thioflavin S-stained Ab plaques. 11  at 40 min after injection was lower than that observed in ArcSwe brain but, when present, also localized around the cores of thioflavin S-positive Ab deposits.
Ex vivo autoradiography with radiolabeled RmAb158-scFv8D3 visualized the presence of the ligand in most parts of the brain. There was especially high retention of the radioligand in cortex, hippocampus, and thalamus already in the baseline groups in both ArcSwe and App NL-G-F mice (Fig. 3A). The spatial distribution of the radioligand did not change because of NB-360 or vehicle treatment, but the intensity of the radioactive signal was lower in the NB-360 and baseline ArcSwe and App NL-G-F mice than in vehicletreated animals. This trend was also evident when the complete postmortem right hemispheres (from which brain sections were prepared) were measured in a g-counter, although the difference did not reach significance because of large interindividual variation (Fig. 3B). Ab42 staining visualized Ab-affected brain regions, and further, the overlap between pathology-rich brain regions and radiolabeled RmAb158-scFv8D3 strongly indicated a colocalization between the radioligand and Ab-affected regions in both mouse models (Fig. 3A). NTE in combination with triple staining of glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and Ab is shown in the Supplemental Figure 4.
Brain homogenates of all animals that underwent PET or SPECT were biochemically assessed with ELISA. Tris-buffered saline (TBS)-soluble Ab aggregates were quantified after centrifugation at 16,000g and 100,000g (Figs. 4A and 4D). In the 16,000g fractions, NB-360-treated ArcSwe animals showed lower levels of Ab aggregates than did the vehicle group (P 5 0.0029), whereas this difference was not significant in the App NL-G-F mice (P . 0.99). However, this decrease was more distinctive and significant in both animal models in the 100,000g fraction (P , 0.0001) representing smaller and more soluble aggregates. In addition, the NB-360 groups displayed lower Ab levels in 100,000g fractions than did the baseline groups (P , 0.0001). Ab1-40 and Ab1-42 in the formic acid fraction represent TBSinsoluble Ab, including fibrils, and thus represent total plaque load (Figs. 4B and 4E). NB-360-treated App NL-G-F , but not ArcSwe, displayed lower Ab1-40 levels than vehicle-treated animals, whereas Ab1-42 levels were decreased in NB-360-treated animals compared with vehicle animals in both models. Correlations between PET/SPECT SUV and Ab levels are included in Supplemental Tables 2-5. Microglial activation was assessed by quantification of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the 16,000g fraction (Figs. 4C and 4F). BACE-1 inhibition decreased sTREM2 levels compared with vehicle in both models (P , 0.0001). In the ArcSwe animals, which showed higher sTREM2 levels than the App NL-G-F animals at baseline, NB-360 treatment also reduced sTREM2 levels compared with baseline (P 5 0.0143).

DISCUSSION
Amyloid imaging has become an important inclusion criterion in clinical trials of candidate drugs aimed at reducing brain Ab. Established amyloid radioligands, such as 11 C-PiB, bind to Ab fibrils deposited as insoluble plaques in the AD brain. These established radioligands may therefore be insufficient for monitoring changes in more soluble or diffuse forms of misfolded and aggregated Ab, which are likely to be affected first by anti-Ab drugs. In this study, we demonstrated that radiolabeled bispecific antibody RmAb158-scFv8D3, binding to soluble Ab aggregates, was able to quantify changes in brain Ab levels after treatment with BACE-1 inhibitor NB-360 in 2 mouse models of Ab pathology and, further, that the readout was different from that of 11 C-PiB PET, which did not detect any differences between treated and untreated groups.
The NB-360 treatment was started at an age when Ab brain pathology was already advanced and the brain tissue, at least in the ArcSwe mice, included large amounts of dense-core Ab deposits. Thus, it may not be surprising that the 11 C-PiB signal did not decrease with treatment, as these deposits are likely to be difficult to dissolve. In line with this observation, formic acid-soluble Ab1-40, the main constituent of dense-core deposits (31), displayed the smallest difference between treatment groups. However, it was somewhat surprising that despite BACE-1 inhibition, leading to a dramatic reduction of the smallest aggregates as shown by ELISA in the 100,000g TBS fraction, the 11 C-PiB signal tended to increase from baseline to the end of treatment. This findings implies that RGB FIGURE 3. Ab42 immunohistochemistry and ex vivo autoradiography of 124/125 I-RmAb158-scFv8D3 in brain tissue. (A) Comparison of Ab42 staining and autoradiography on sagittal brain sections of 1 representative ArcSwe or App NL-G-F animal of each studied group. Stained brain section was merged to overlay with corresponding ex vivo autoradiography of same animal to visualize pathology and tracer binding simultaneously. (B) Postmortem ex vivo quantification of 124/125 I-RmAb158-scFv8D3 in complete right hemisphere in ArcSwe and App NL-G-F animals.
once insoluble deposits have been formed, they may continue to increase in number and size, especially if the pool of monomers and nonfibrillar aggregates has not been completely depleted. As illustrated by the ELISA measurements, the reduction in intermediate-sized Ab aggregates, that is, the 16,000g fraction, was either smaller than that observed for the soluble aggregates in the 100,000g fraction (ArcSwe) or absent (App NL-G-F ). A longer treatment time may be required to remove also the 16,000g aggregates. This hypothesis is supported by clinical studies of BACE-1 inhibitors that have reported decreased brain amyloid levels detected with PET after 1.5-2 y of treatment (32,33).
The spatial distribution of 124 I-RmAb158-scFv8D3 studied by ex vivo autoradiography in combination with Ab42 immunohistochemistry indicated radioligand accumulation in Ab-rich brain regions in both mouse models. In contrast, ex vivo autoradiography with 11 C-PiB was evident in regions with abundant Ab pathology only in the ArcSwe model, not in the App NL-G-F model. The main reason for selecting these 2 models for the present study was their dissimilar Ab profiles, illustrated by their very different relative ratios of Ab40 and Ab42; Ab40 is the major Ab species in ArcSwe mice, whereas Ab42 dominates in App NL-G-F mice (Fig. 4). It has been shown that although Ab42 is more prone to aggregate, the dense core of plaques is formed by Ab40 (31). It should also be noted that Ab40 is the major Ab isoform produced in human sporadic AD (34). Thus, this fact leads to another important aspect highlighted in the present study, that is, the selection of animal models for preclinical studies of brain Ab, especially when evaluating the ability of candidate drugs to reduce pathologic changes. The application of 11 C-PiB, and analogs, in animal studies has indeed been debated over the last 10-15 y. First, preclinical attempts to quantify Ab deposits with 11 C-PiB in the PS1/APP transgenic mouse model resulted in contradictory results claiming structural differences between Ab plaque formation and cerebral pathology in mice and humans (35). Yet, more recent studies have demonstrated that Ab deposits can be assessed by 11 C-PiB in mouse models such as APP23 (36,37) and APP/PS1-21 (38). Further, several studies with 18 F-labeled analogs of 11 C-PiB have underlined the ability of Ab plaque assessment in different mouse models (39), especially in longitudinal studies (21,40). Several studies have reported the ability of amyloid PET to quantify disease-modifying treatments, for example, mApoE-pA-Lip in APP23 mice (41) and BACE-1 inhibition in PS2APP mice (42). Thus, the use of amyloid PET likely requires a model with dense-core Ab deposits. The present study also demonstrated that weak 11 C-PiB binding is not per se a sign of low brain Ab levels, as radiolabeled RmAb158-scFv8D3 was readily able to detect the abundant Ab pathology in 11 C-PiB-negative App NL-G-F mice both in vivo and ex vivo. In line with this observation, patients with AD caused by specific mutations in the AbPP, with confirmed diffuse pathology and absence of dense-core plaques, have also been reported as 11 C-PiB-negative (7). Again, this finding illustrates the need for radioligands able to quantify Ab in forms other than insoluble deposits (plaques).
We used SUV, that is, activity concentrations normalized to the injected activity per body weight, as the main readout measure from PET. This is different from most studies that have reported SUVRs-that is, activity ratios between regions of interest and a reference region. The reference region used in previous studies has in most cases been cerebellum or periaqueductal gray matter (21). However, in the present study, Ab pathology was spread in the whole brain at the start of the study, hence excluding the use of a pathology-free region as a reference. In addition, all brain regions, including cerebellum and periaqueductal gray matter, were affected by disease progression and by NB-360 treatment as shown by PET/SPECT and autoradiography and by ELISA of postmortem cerebellum homogenates (Supplemental Fig. 5). Thus, in this setting it was not possible to use reference region-based methods.
Apart from Ab, brain sTREM2 concentrations were also investigated in brain homogenates and found to be decreased in both mouse models after administration of NB-360. This finding suggests an extenuating effect on microglia activation due to lower Ab production and aggregation.

CONCLUSION
Antibody-based PET and SPECT imaging of soluble Ab aggregates is a sensitive tool to follow Ab pathology in the brain. This study demonstrated the ability of such ligands to quantify changes due to anti-Ab treatment at a stage of advanced Ab pathology. Thus, radioligands based on antibodies directed toward a specific form of aggregated Ab may have potential to improve and complement diagnostics in preclinical and clinical studies of AD drug candidates. We demonstrated in this study that radiolabeled RmAb158-scFv8D3 is able to quantify changes in brain Ab levels after BACE-1 inhibition in 2 AD mouse models, and further, that the readout is different from that of 11 C-PiB.

DISCLOSURE
This work was supported by grants from the Swedish Research Council (2017-02413 and 2018-02715), Alzheimerfonden, Hj€ arnfonden, Torsten S€ oderbergs stiftelse, Åhl enstiftelsen, Magnus Bergwalls stiftelse, Stiftelsen f€ or gamla tj€ anarinnor, and Konung Gustaf V:s och Drottning Victorias Frimurarestiftelsen. The funding bodies did not take part in design of the study; in collection, analysis, or interpretation of data; or in writing of the manuscript. The molecular imaging work in this study was performed at the SciLifeLab Pilot Facility for Preclinical PET-MRI, a Swedish nationally available imaging platform at Uppsala University, Sweden, financed by the Knut and Alice Wallenberg Foundation. Ulf Neumann is an employee and shareholder of Novartis Pharma AG, Basel, Switzerland. No other potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS
We thank Dr. Derya Shimshek, Novartis, for supplying the NB-360 food pellets; Prof. Lars Nilsson for developing the ArcSwe mouse model used in this study; and BioArctic for sharing the mAb158 sequence.

KEY POINTS
QUESTION: Do 11 C-PIB and 124 I-antibody PET readouts provide differing estimates of brain Ab after therapeutic intervention in ArcSwe and App NL-G-F mice with pronounced Ab pathology, and if they do, what is the implication for drug development for AD?
PERTINENT FINDINGS: The antibody-based radioligand detected changes in brain Ab levels after anti-Ab therapy in ArcSwe and App NL-G-F mice. In contrast, the decreased Ab levels could not be quantified with gold-standard 11 C-PiB PET, suggesting that these ligands detect different pools of Ab.
IMPLICATIONS FOR PATIENT CARE: Radioligands based on antibodies directed toward a specific form of aggregated Ab may have potential to improve and complement diagnostics in preclinical and clinical studies of AD drug candidates.