Glitter in the Darkness? Non-fibrillar β-amyloid Plaque Components Significantly Impact the β-amyloid PET Signal in Mouse Models of Alzheimer's Disease.

Biechele, Gloria; Sebastian Monasor, Laura; Wind, Karin; Blume, Tanja; Parhizkar, Samira; Arzberger, Thomas; Sacher, Christian; Beyer, Leonie; Eckenweber, Florian; Gildehaus, Franz-Josef; von Ungern-Sternberg, Barbara; Willem, Michael; Bartenstein, Peter; Cumming, Paul; Rominger, Axel; Herms, Jochen; Lichtenthaler, Stefan; Haass, Christian; Tahirovic, Sabina and Brendel, Matthias (2022). Glitter in the Darkness? Non-fibrillar β-amyloid Plaque Components Significantly Impact the β-amyloid PET Signal in Mouse Models of Alzheimer's Disease. Journal of nuclear medicine, 63(1), pp. 117-124. Society of Nuclear Medicine 10.2967/jnumed.120.261858

jnumed.120.261858.full.pdf - Accepted Version
Available under License Publisher holds Copyright.

Download (2MB) | Preview
117.full.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview

Objective: β-amyloid PET (Aβ-PET) is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer's disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ-PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and non-fibrillar Aβ components to the in vivo Aβ-PET signal remain unclear. Thus, we obtained two murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ-PET signal in vivo. Methods: We investigated groups of AppNL-G-F and APPPS1 mice at three, six and 12 months of age by longitudinal 18F-florbetaben Aβ-PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group level inter-modality regression models using age and genotype matched sets of fibrillar/ non-fibrillar Aβ data (predictors) and Aβ-PET results (outcome) for both transgenic models. An independent group of double-hit APPPS1 mice with dysfunctional microglia due to knock-out of triggering receptor expression on myeloid cells 2 (Trem2-/-) served for validation and evaluation of translational impact. Results: Neither fibrillar nor non-fibrillar Aβ content alone sufficed to explain the Aβ-PET findings in either transgenic AD model. However, a regression model compiling fibrillar and non-fibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ-PET signal (P<0.001). Fibrillar Aβ burden had a 16-fold higher contribution to the Aβ-PET signal when compared to non-fibrillar Aβ. However, given the relatively greater abundance of non-fibrillar Aβ, we estimate that non-fibrillar Aβ produced 79±25% of the net in vivo Aβ-PET signal in AppNL-G-F mice, and 25±12% in the APPPS1 mice. Corresponding results in separate groups of APPPS1/Trem2-/- and APPPS1/Trem2+/+ mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ-PET signal. Conclusion: Taken together, the in vivo Aβ-PET signal derives from the composite of fibrillar and non-fibrillar Aβ plaque components. While fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of non-fibrillar Aβ plaque in AD model mice contributes importantly to the PET signal.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Cumming, Paul and Rominger, Axel Oliver


600 Technology > 610 Medicine & health




Society of Nuclear Medicine




Daria Vogelsang

Date Deposited:

10 Jan 2022 10:54

Last Modified:

10 Jan 2022 11:02

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Animal Imaging Neurology PET PET signal amyloid fibrillar mouse non-fibrillar




Actions (login required)

Edit item Edit item
Provide Feedback