Slemann L, Gnorich J, Hummel S, Bartos LM, Klaus C, Kling A, Kusche-Palenga J, Kunte ST, Kunze LH, Englert AL, Li Y, Vogler L, Katzdobler S, Palleis C, Bernhardt A, Jäck A, Zwergal A, Hopfner F, Romer S, Biechele G, Stocklein S, Bischof G, vanEimeren T, Drzezga A, Sabri O, Barthel H, Respondek G, Grimmer T, Levin J, Herms J, Paeger L, Willroider M, Beyer L, Hoglinger GU, Roeber S, Franzmeier N, Brendel M. Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies. 2024 May 07 10.1101/2024.05.04.592508 (version 1) bioRxiv.
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Centre for Addiction and Mental Health & University of Toronto
18FPI-2620 was developed to image aggregated tau with mixed 3- and 4-microtuble-binding repeat domains (3R- and 4R-tau) in patients with Alzheimer’s disease (AD), and has recently been applied to patients with 4R-tauopathies, such as progressive supranuclear palsy (PSP). This elegant study sheds light on the mechanism of binding of 18FPI-2620 with PET and autopsy studies that show a strong correlation of regional 18FPI-2620 signals to abundance of fibrillary tau. Furthermore, in vivo imaging with 18FPI-2620 in a transgenic mouse model of 4R-tau was followed by an innovative cell-sorting approach to determine radiotracer uptake by cell type (neurons vs. astrocytes) and validates the claims of high specificity of this radiopharmaceutical for intraneuronal tau in human PET studies. It will be interesting to apply the cell-sorting method to next-generation tau-PET radiotracers that our laboratories and others are developing for non-AD tauopathies, such as 18FOXD-2314, which is planned for first-in-human testing at our center in the next few weeks.
View all comments by Neil VasdevVU University Medical Center
Like other tau PET tracers, for example MK6240, flortaucipir, and RO948, PI2620 has shown excellent diagnostic performance in distinguishing symptomatic AD from other neurodegenerative disorders. An open question is whether PI2620 can also be utilized for diagnostic purposes in individuals with a primary 4R tauopathy, such as progressive supranuclear palsy (PSP).
This preprint describes very elegant and well-executed experiments showing 1) increasing PI2620 signal in a 4R (PS19) mouse model in the presence of high neuronal tau, 2) good correlations between antemortem PI2620 signal versus postmortem fibrillary tau in autopsy samples of PSP patients, and 3) that the PI2620 signal in PSP is mainly driven by tau-positive neurons and oligodendrocytes (but not astrocytes) as defined by autoradiography.
This main implication of this work is that it provides a better understanding about the source of PI2620 binding in individuals with PSP. I am not convinced yet that the in vivo signal of this tracer is strong and robust enough for offering diagnostic and/or prognostic value at the individual level in suspected primary 4R tauopathies. This is based on the substantial signal overlap described in previous studies between PSP cases and controls/other movement disorders, even in PSP signature regions such as the globus pallidus and putamen. However, I am happy to be proven wrong, since robust molecular biomarkers for primary tauopathies are desperately needed.
View all comments by Rik OssenkoppeleNational Institute of Radiological Sciences
In this work, Slemann and colleagues utilized tau-transgenic mice and brain sections derived from PSP patients who had undergone PET scans, along with sections from a brain bank, to demonstrate the ability of a tau PET probe, 18FPI2620, to capture four-repeat (4R) tau aggregates in the brain. The non-clinical assessments in animals would provide unequivocal evidence for the reactivity of the probe with the target components, since in vivo PET and postmortem data could be compared in the same subject with a minimal chronological gap between the two assays. While the authors’ efforts to prove the binding of 18FPI2620 to 4R tau assemblies are acknowledged, several methodological issues need to be figured out before reaching any conclusions.
The PS19 transgenic mice employed in the PET analysis develop only a limited number of densely packed, thioflavin-S- and FSB-positive neuronal tau inclusions in the hippocampus, entorhinal, and retrosplenial cortices, and in the amygdala. These may not be readily detectable by PET, despite numerous AT8-positive phosphorylated tau deposits in these locations. Such mature tau deposits are more abundant in the brainstem and spinal cord, but PET of these pathologies is often challenging due to small volumes of the target anatomical structures. In the current investigation, marked radioactivity spillover from neighboring extracranial space was noted in the cerebellum, brainstem, amygdala, entorhinal cortex, and olfactory bulb of transgenic and wild-type mice, although the amount of radio signal outside the brain was not shown in the trimmed PET images. The spillover effect could be more pronounced if the brain parenchyma displays atrophy. Even with the authors taking great care in defining the regions of interest by eroding them, the radioactivity spread from surrounding tissues may be nearly unavoidable.
The measurement of radioactivity uptake in isolated neurons and astrocytes are also interesting approaches, however, the normalization of the observed values may not be simple. The radiotracer uptake per single cell was determined as percent injected dose (ID)/g sample, which might be influenced by the body weight of the animal (increased by the weight loss) and by the number and volumes of the cells in the unit tissue (possibly decreased in astrocytes if they are hypertrophic and proliferate). Accordingly, the percent ID/g values in the cellular assay may not be directly compared with the target-to-reference ratio of the radioactivity retention (SUVR) in PET quantifications.
The autoradiography of the samples from scanned subjects offers highly valuable information on the molecular and cellular sources of the in vivo radio signals, and the establishment of robust techniques for evaluating the tracer binding in the brain sections should be an essential requirement. It remains to be assessed whether the autoradiographic labeling of subregions enriched with tau pathologies can be displaced by an excess concentration of non-radiolabeled PI-2620. It should also be clarified why basal ganglia and frontal cortex sections equally exhibited low radiotracer binding in the control brain despite profound, nonspecific, in vivo radioactivity retention in the basal ganglia and thalamus. Of note, the intensification of the autoradiographic signals around the boundary between gray and white matter of the frontal cortex was in line with PET data showing the locally highest Cohen’s d (0.5 – 0.7) in this cortical segment for the separation between PSP patients and controls. One would like to know the diagnostic significance of this finding, as this effect size usually translates to an AUC of ~0.7.
Studies have shown that tau aggregates in PSP and other 4R tauopathies and 4R tau-expressing tau transgenics, e.g., rTg4510 mice, can be visualized with high contrast by PET with 18Fflorzolotau, aka APN-1607/PM-PBB3, which binds to the cross-β structure commonly shared by diverse tau fibril folds. Besides this radiotracer, PET probes reacting with fibrils in primary tauopathies that have a different binding mode would exert superb diagnostic performance with high selectivity for tau versus other protein assemblies. Evaluations of 18FPI-2620 may bring clues to the development of such tau ligands, and refinements of PET and autoradiographic examinations in the research community will be a high-priority issue.
View all comments by Makoto HiguchiMake a Comment
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