Glitter in the Darkness? Nonfibrillar β-Amyloid Plaque Components Significantly Impact the β-Amyloid PET Signal in Mouse Models of Alzheimer Disease

Abstract

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 App NL-G-F and APPPS1 mice at three, six and 12 months of age by longitudinal 18 F-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 nonfibrillar Aβ, we estimate that non-fibrillar Aβ produced 79±25% of the net in vivo Aβ-PET signal in

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition

“…For all mice, behavioral testing after the terminal PET scan was followed by immunohistochemical and biochemical analyses of randomized hemispheres. The TSPO-PET arm of the study and detailed analyses of neuroinflammation imaging are reported in a separate manuscript focusing on the predictive value of TSPO-PET for outcome of PPARγ-related immunomodulation ( Biechele et al, 2022 ). The sample size estimation of the in vivo PET study was based on previous experience and calculated by G*power (V3.1.9.2, Kiel, Germany), assuming a type I error α = 0.05 and a power of 0.8 for group comparisons, a 10% drop-out rate per time-point (including TSPO-PET), and a treatment effect of 5% change in the PET signal.…”

“…Components with an Eigenvalue >1.0 were extracted and a varimax rotation was selected. Water maze results were also used as an endpoint in the dedicated manuscript on serial TSPO-PET in both cohorts ( Biechele et al, 2022 ). For immunohistochemistry quantifications GraphPad Prism (GraphPad Software, San Diego, California, United States) was used.…”

Regional Associations of Cortical Superficial Siderosis and β-Amyloid-Positron-Emission-Tomography Positivity in Patients With Cerebral Amyloid Angiopathy

“…Hence, signal loss due to atrophy could be another confounder of the observed decreased SUVr. Then, the altered plaque morphology in terms of reduced Aβ plaque density could also lead to a reduced signal in PET (Biechele et al, 2021). In this regard, we noted that diffuse and vascular Aβ occurring at cSS sites provides fewer tracer binding sites when compared to cored Aβ plaques which could, in turn, hamper the detection by PET.…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…One of the unsolved question in Aβ imaging is the detection towards small forms of A aggregates. Biechele et al recently indicated that the non-fibrillar Aβ (positive for 3552 antibody) in addition to the Thiazine red stained fibrillar Aβ significantly impacted the [ 18 F]florbetaben PET signal in App NL-G-F and APP/PS1 mice from 3-12 month-of-age [68].…”

“…RN wrote the manuscript and approved the submission. APP/PS1 mice [40,60,82,86,[246][247][248] 3×Tg mice [249] APP23 mice [37,60,190] Aged non-human primate TASTPM mice [250] APP/PS1 mice [73,251] [ 18 F]florbetaben, AV-1 PS2APP mice [61,252] APPswe mice [61,253] App NL-G-F mice [68,192,197,252,254] APPswe/PS1G384A mice [61] APP-SL70 mice [252,255] TgF334 rats [152] APP/PS1 mice [61,68,82,256] [ 11 C]AZD2184 APPswe mice [244] APP/PS1 mice [257] [ 18 F]flutafuranol AZD4694, NAV4694…”