Neuronal injury assessment with early-phases of [18F]PI-2620 tau-PET versus [18F]flutemetamol β-amyloid-PET recordings

doi:10.21203/rs.3.rs-1995495/v1

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Research Article

Neuronal injury assessment with early-phases of [18F]PI-2620 tau-PET versus [18F]flutemetamol β-amyloid-PET recordings

https://doi.org/10.21203/rs.3.rs-1995495/v1

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Journal Publication

published 27 Dec, 2022

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Purpose

Characteristic features of β-amyloid-PET (A), tau-PET (T) and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of β-amyloid- or tau-PET recordings serve as surrogates for cerebrometabolic deficits to FDG-PET, therefore indicate neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase β-amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [¹⁸F]flutemetamol β-amyloid-PET and [¹⁸F]PI-2620 tau-PET as “one-stop shop” dual purpose tracers for detection of neurodegenerative disease.

Methods

We obtained early-phase PET recordings with [¹⁸F]PI-2620 (0.5–2.5 min p.i.) and [¹⁸F]flutemetamol (0–10 min p.i.) in 66 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes-of-interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Spearman’s rank correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < -3) and patients with different neurodegenerative disease entities (e.g., Alzheimer’s disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional neuronal injury with clinical tests.

Results

The z-scores of perfusion-weighted images of both tracers showed high correlations across brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced neuronal injury (R = 0.83 ± 0.08; range: 0.61–0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range: 0.16–0.90), notably when significant neuronal injury was present (R = 0.66 ± 0.15; range: 0.28–0.90).

Conclusion

The early perfusion phases of tau- and β-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve as a comparable diagnostic channel in the A/T/N classification framework.

neuroimaging

perfusion phase

[18F]PI-2620

[18F]flutemetamol

β-amyloid

tau

As our society is demographically aging, the incidence of neurodegenerative diseases is on the rise; the Dementia Forecasting Collaborators predict a 166% increase of the global prevalence of dementia in the coming three decades [1]. Treatments under development for neurodegenerative diseases such as Alzheimer’s disease (AD) include anti-β-amyloid-antibodies such as Aducanumab, Donanemab [2, 3]. A timely and precise diagnosis and therapy monitoring of objective endpoints is crucial for the development of successful therapies. Multiple studies have used FDG-PET/CT for localization and quantification of cerebrometabolic defects indicative of neuronal injury during AD treatment trials [4–6]. Furthermore, aggregation of misfolded proteins leading to neuronal damage can be detected years before symptom onset with PET tracers for β-amyloid (Aβ) and tau. Assessments of neuronal injury, Aβ, and tau were recently embedded in the A/T/N scheme in the framework of AD research [7, 8]. This detailed assessment of patients by ATN indices may enable the development of more effective interventions against neurodegeneration [9–11]. While arterial spin-labelling MR or [¹⁵O]-water PET are the standard methods for quantifying cerebral perfusion, the early uptake phase for many molecular imaging tracers contains information about the perfusion rate, and may thus contribute to the A/T/N schema. Thus, PET imaging with β-amyloid or tau tracers can serve a dual purpose for molecular imaging, while also providing a surrogate marker of neurodegeneration. However, no study to date has investigated the comparability of early-phase imaging of tau PET versus Aβ PET as surrogates for impaired perfusion and metabolism. We therefore set out to compare the properties of early phase β-amyloid-PET with [¹⁸F]flutemetamol versus corresponding findings for tau-PET with the second generation tracer [¹⁸F]PI-2620. We tested the hypothesis that the two tracers would be similarly fit for detecting perfusion defects in the early-phase recordings of patients with suspected neurodegenerative disease.

Patient enrolment

All patients who underwent dynamic PET recordings with [¹⁸F]flutemetamol and [¹⁸F]PI-2620 for differential diagnosis of AD and other neurodegenerative diseases at the Department of Nuclear Medicine, LMU Munich seen between 10/2018 and 08/2021 were included in this study. Informed written consent was obtained according to the Declaration of Helsinki. The retrospective study was approved by the institutional human experimental ethics committee (application number 17-569).

Radiosynthesis and image acquisition

Radiosynthesis of [¹⁸F]flutemetamol was performed as described previously [12]. [¹⁸F]PI-2620 was synthesized using a BOC-protected nitro-precursor automated synthesis module (IBA, Synthera). After semipreparative high performance liquid chromatography radiochemical purity was > 97%. Yields were about 30% with a molar activity of 3x10⁶ GBq/mmol.

PET data were acquired with a Biograph 64 or a Siemens mCT PET/CT scanner (Siemens Healthineers, Erlangen, Germany) at the Department of Nuclear Medicine, LMU Munich. The [¹⁸F]flutemetamol acquisition was conducted in two phases, with a perfusion-weighted scan during 0-10 minutes post injection, followed by a second dynamic recording during 90-110 minutes post injection [13]. The [¹⁸F]PI-2620-PET acquisition consisted of a dynamic recording during 0-60 minutes post injection. Mean injected activity was 191 MBq (range: 151-223 MBq) for [¹⁸F]PI-2620-PET and 185 MBq (range: 124-219 MBq) for [¹⁸F]flutemetamol.

Image processing and analysis

Perfusion phase images were reconstructed during 0-10 min p.i. for [¹⁸F]flutemetamol-PET and 0.5-2.5 min p.i. for [¹⁸F]PI-2620-PET and summarized to a single frame, following precedent for selection of the perfusion weighted evaluations [9, 13]. For spatial normalization, perfusion-weighted images were registered to the template of a healthy control cohort using the PMOD Fusion tool (version 3.5, PMOD Technologies, Zurich, Switzerland). The control cohort (n=15) was selected from among β-amyloid and tau-negative scans from previous studies [14, 15]. For each scan, we obtained segmentation of the SUV maps for each of the 246 brain regions defined by the Brainnetome atlas [16], which were extracted using the PMOD View tool. SUV ratios (SUVr) were computed relative to the respective global mean uptake and cerebellar uptake using a Matlab script [9, 13, 17]. Regional group differences in tracer uptake (z-scores) were computed for both tracers by contrasting the mean SUVrs by region in the patient versus control groups. Pearson’s correlation coefficients between respective z-scores of early-phase [¹⁸F]flutemetamol- and [¹⁸F]PI-2620-PET recordings were evaluated by region with GraphPad Prism (version 8.4.3 (686)). We also evaluated mean lobular z-scores in bilateral frontal (n=34 Brainnetome regions each side), temporal (n=28 regions each side), parietal (n=19 regions for each side), and occipital regions (n=11 regions each side). Patients with significant neuronal injury (> 5 regions with z-Scores < -3) and patients with different entities of neurodegenerative diseases (AD vs. 4R-tauopathies) served for subgroup analysis.

Patient collective

64 patients underwent two-phase [¹⁸F]flutemetamol-PET and dynamic [¹⁸F]PI-2620-PET investigations, with an average time gap of 3.2 months (range: 37 – 545 days). All patients had been referred for PET imaging by local specialists due to suspicion of neurodegenerative disease. Mean age was 69 years (±8.5; range: 46-87). 25 patients were clinically diagnosed with corticobasal syndrome [18], 21 with AD [8] ten with progressive supranuclear palsy [19], one with primary progressive aphasia, two with frontotemporal dementia [20, 21], one with Parkinson’s disease, one with vascular dementia, two with subjective memory complaints, and one with mild cognitive impairment without underlying AD pathology. Tau-PET analysis and separate analysis of early-phase imaging of both tracers were reported in previous investigations [9, 13-15, 22].

Regional comparison of early-phase [¹⁸F]flutemetamol and early-phase [¹⁸F]PI-2620 in different brain regions

All cortical brain regions and the evaluated subcortical regions (basal ganglia) showed high correlations of early-phase [¹⁸F]PI-2620 and [¹⁸F]flutemetamol SUVr values, with the highest correlations in the left parietal lobe (r = 0.930; p < 0.0001), and the lowest in the left temporal lobe (r = 0.775; p < 0.0001). Correlation plots by lobe are shown in Figure 1. The correlations for all single regions using global mean scaling as well as cerebellar scaling (as a cross-validation) are shown in Supplementary table 1 and 2.

Correlation between early phases of tau-PET and β-amyloid-PET in dependence of the regional neuronal injury burden

The agreement between early-phase tau-PET and β-amyloid-PET results was significantly lower in regions with less severe perfusion defects as indicated by lower z-score: There was a moderate correlation of the mean z-score of the individual Brainnetome regions (n=246) assessed in [¹⁸F]flutemetamol-PET and [¹⁸F]PI-2620-PET and the correlation of both early-phase indices in the specific Brainnetome regions (r = 0.479; p < 0.0001). Figure 2A shows the mean regional z-scores against the regional correlations for both early-phase PET recordings.

Correlation between early phases of tau-PET and β-amyloid-PET in dependant of the region volume

The predefined Brainnetome regions had volumes between 0.67 cm³ and 12.41 cm³. Correlations between early phase uptakes of the two tracers were higher in the larger brain regions the (Figure 2B), giving a moderate positive correlation between the correlation between early-phase [¹⁸F]flutemetamol-PET and [¹⁸F]PI-2620-PET z-scores as a function of the size of region when evaluating global mean scaled data (r = 0.364; p < 0.0001).

Correlation of early-phases of tau-PET and β-amyloid-PET in specific subgroups of patients with Alzheimer’s disease and 4-repeat tauopathies

The correlation of perfusion surrogates using early-phase [¹⁸F]flutemetamol-PET [¹⁸F]PI-2620-PET did not significantly differ (p = 0.627) between patients with AD (r = 0.843-0.963) and patients with 4-repeat tauopathies (r = 0.746-0.932) (Figure 3). In particular, patients with AD showed the highest correlations in the parietal lobe, the frontal lobe (excluding the motor strip), the anterior cingulate gyrus, the putamen and the caudate nucleus, as well as the superior and middle temporal gyrus, equally for both tracers. Patients with 4-repeat tauopathies showed the highest correlation in the parietal lobe, the frontal lobe, the anterior and the posterior cingulate gyrus, and the caudate nucleus and the putamen, as well as the insula and the mesial occipital lobe, irrespective of the used tracer.

Correlation between cognitive screening performance and neuronal injury assessment by early phase tau- and β-amyloid-PET in patients with Alzheimer's disease

For 11 of 21 patients suffering from AD, MMSE scores were available at the time of imaging (mean score: 23.7; median 25.5, range: 12-30). Partial regression corrected for age and gender showed that MMSE was a significant predictor (p < 0.05) for the early-phase [¹⁸F]flutemetamol z-score results in Brainnetome regions of the inferior parietal cortex (9/12 regions), the mesial precuneus (3/4 regions), the caudal and dorsal area of the posterior cingulate gyrus (3/4 regions), and the orbitofrontal cortex (9/12 regions) (Figure 4). The single region partial correlation coefficient Rho ranged from 0.678 to 0.943 (median = 0.749). The partial regression evaluated for the perfusion phase of [¹⁸F]PI-2620 PET showed a significant correlation of MMSE and the z-scores in the same lobes, but involving fewer subregions, e.g. in the inferior parietal regions (7/12 regions), the mesial precuneus (3/4 regions), the caudal and dorsal area of the posterior cingulate gyrus (3/4 regions), and the orbitofrontal cortex (5/12 regions). The magnitude of Rho ranged from 0.667 to 0.884 (median = 0.684). The regions where z-scores correlated significantly with MMSE scores were similar for early phase tau- and β-amyloid-PET (p = 0.181, Χ²).

Correlation between symptom severity and neuronal injury assessment by early phase tau- and β-amyloid-PET in patients with 4-repeat tauopathies

31 out of 35 patients with 4-repeat tauopathies (PSP/CBS) had been assessed according the PSP rating scale (PSPRS) at the time of imaging (Figure 5). PSPRS scores were a significant predictor (p < 0.05) of the apparent perfusion deficit of 21/246 regions in [¹⁸F]flutemetamol- and 19/246 regions in [¹⁸F]PI-2620-PET. The affected regions in these patients consisted mainly of subcortical regions, including the caudate nucleus and the thalamus (4/28 and 7/28 regions), as well as the anterior cingulate gyrus (3/8 and 5/8 regions). Additionally, a few regions of the (inferior) frontal lobe showed a significant correlation (10/68 and 5/68 regions). The Rho of single regions ranged between 0.39 and -0.65 (median: -0.43). The regions where z-scores correlated significantly with PSPRS scores were similar for early phase tau- and β-amyloid-PET (p = 0.741, Χ²).

Previous studies have shown a high correlation between the perfusion phase uptake of β-amyloid and tau-PET tracers with the extent of regional neuronal injury to FDG-PET [9–11, 23–26]. These relationships are relevant in the context of flow-metabolism coupling, and the cerebrometabolic deficits occurring in AD and other neurodegenerative conditions. Indeed, cerebral perfusion-PET still has a role in the diagnosis of AD [27], although the regional relationship between perfusion and metabolic rate is imperfect [28]. A comprehensive imaging biomarker-based diagnostic workup in patients with neurodegenerative diseases may include FDG-PET, as well as β-amyloid-PET and tau-PET, for a classification within the A/T/N scheme, namely β-amyloid PET or CSF β-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N) [7]. The opportunity for “one-stop-shop” PET examinations providing information about specific pathology and general decline in cerebral perfusion/metabolism within the setting of a single PET examination would offer many advantages both for the patient and for health care systems: First, a time-consuming and costly examination can be spared. Second, the radiation exposure to patients is reduced. Finally, there is no requirement for fasting prior to β-amyloid or tau-PET, which could be problematic for patients with poor glucose control. The current results additionally suggest the possibility of using early-phase β-amyloid PET or early-phase tau-PET as surrogates for perfusion imaging. Comparable assessment of regional neuronal injury by early phase of tau- and β-amyloid-PET potentially enable tracking longitudinal changes by serial PET examination with different tracers at different time-points. This has clinical relevance since β-amyloid-PET can serve as early diagnostic biomarker of AD pathology [29]. On the other hand, tau-PET is more likely to be employed in patients with more advanced cognitive decline, since tau-PET signals have a more robust correlation with cognitive impairment [30].

For evaluation of the comparability of early phase β-amyloid-PET and tau-PET as markers of perfusion deficit, we investigated the correlation of the two markers across single brain regions. For subgroup analysis, we divided the patients into groups with AD or 4-repeat tauopathies. Furthermore, we evaluated the impact on these relationships of volume of evaluated regions, severity of perfusion deficit, and clinical symptoms using established clinical scores.

We found strong to excellent correlations between early-phases of tau-PET and β-amyloid-PET in the neocortical regions and in most of subcortical regions. In general, the correlation was strongest in lobes, regions, and patients with a significant perfusion deficit. First, there was a moderate negative correlation of the z-score in single Brainnetome regions and the correlations between early-phase β-amyloid-PET and tau-PET, thus showing that a more severe perfusion deficit was associated with a higher correlation between early-phase tau-PET and amyloid-PET. Second, among the four great lobes, the correlations between early phase β-amyloid-PET and tau-PET were highest in the frontal and parietal lobes. This is in line with more severe neuronal damage in the frontal lobe, manifesting in a lower average z-score (frontal: -0.315; parietal: -0.615; temporal: +0.485; occipital: +0.310). Third, sub-analysis of single Brainnetome regions showed the best correlation in known predilection sites of neuronal damage in patients with Alzheimer’s disease, e. g. the precuneus [31]. The improved correlation in regions with a more severe perfusion deficit follows from the relatively higher amplitude of the z-scores, with additional effects arising from factors such as spatial resolution, partial volume effects, and image reconstruction procedures.

In another sub-analysis, the perfusion surrogates from the two tracers correlated equally well in patients with different entities of neurodegenerative diseases, e. g. AD and 4-repeat tauopathies, which shows the robustness of our approach irrespective of the particular diagnosis. This result is consistent with recent findings showing that FDG-PET and the perfusion phases of β-amyloid or tau-PET were comparable for identifying patients with different neurodegenerative diseases [9, 11, 13].

Additionally, we investigated the correlation between perfusion surrogates as a function of the volume of the brain region. The two perfusion surrogates were more similar in larger regions than in small regions. That relationship is explainable by the greater quantitative robustness and lesser vulnerability to partial volume effects of larger structures. Furthermore, we investigated the partial regression of clinical severity scores for AD and PSP with the z-scores in the Brainnetome regions, corrected for age and gender. We found that in the AD group, the MMSE scores were a significant predictor for z-scores in AD predilection sites. Patients with 4-repeat tauopathies similarly showed a significant relationship between their PSPRS scores and the corresponding z-scores in PSP signature regions like the basal ganglia and the limbic lobe. This is in accord with recent results from our group indicating a high correlation between perfusion deficit and the PSP rating scale scores in patients with 4R-tauopathies [22]. Thus, perfusion-weighted imaging with [¹⁸F]flutemetamol or [¹⁸F]PI-2620 can serve for monitoring disease severity, irrespective of their properties as molecular imaging agents with specific for β-amyloid or tau.

Potential limitations of this study arise from the variable time interval between acquisitions of the early-phase β-amyloid and tau- PET imaging. A gap of as much as 18 months might well have been accompanied by disease progression, to the detriment of correlations between early phase PET results. Another limiting factor in this study is the lack of histopathological data, which might have established a certain diagnosis. Furthermore, we only considered cognitive screening at the time of imaging which resulted in a low number of MMSE scores in the AD cohort. However, given the known strong association between neuronal injury and cognitive performance in AD [32, 33], this sample size was sufficient to assess the comparability of regional early-phase tau-PET and early-phase β-amyloid-PET correlations with MMSE. Our use of early tracer uptake as a surrogate for cerebral perfusion calls for some consideration. The initial brain uptake of any PET tracer is a function of the tracer’s permeability-surface area product and the extraction fraction, which is the ratio of the unidirectional blood brain clearance (K1) to the perfusion rate, F. As such, recordings of initial tracer uptake are an imperfect surrogate of the rate of cerebral blood flow, which is best depicted by tracers with a high extraction fraction. For example, we have shown that initial brain uptake of the dopamine receptor ligand [¹⁸F]fallypride correlated with a more direct index of perfusion rate, thus presenting a useful surrogate for age-dependent reductions in perfusion [34]. Additionally, there was a good correlation between the early perfusion phase uptake of the monoamine oxidase B ligand [¹¹C]deprenyl-d₁ with that of the β-amyloid tracer [¹¹C]PiB in the same individuals PET [35, 36]. Thus, the high initial uptake of [¹⁸F]flutemetamol in rodent brain, peaking at SUV = 5.8 at two minutes post-injection [37] and similarly high uptake for [¹⁸F]PI-2620 in non-human primate brain [38], are indicative of high extraction fraction, which is a necessary precondition for using early phase uptake as a surrogate of perfusion rate.

The early-phases of tau-PET and β-amyloid-PET brain uptake are comparable surrogates of cerebral perfusion deficit, as a biomarker for neuronal injury in neurodegenerative disorders. Uptake in regions of a highly parcellated brain atlas indicated robust agreement between early phases of tau-PET and β-amyloid-PET, especially in signature regions of significant neuronal damage in AD and PSP.

Acknowledgements: We thank the team of Nuclear medicine at LMU Klinikum Munich as well as the patients and their families for participating in the study.

Funding information J.L., S.K. and C.P. received research funding from Lüneburg heritage. S.K., J.L, R.P., C.P., M.B. and P.B. were funded by the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198).

Compliance with ethical standards

Conflict of interest: MB received speaker honoraria from GE healthcare, Roche and LMI and is an advisor of LMI. OS received research support from LMI. HB received reader honoraria from LMI. JL reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, non-financial support from Abbvie and compensation for duty as part-time CMO from MODAG, all outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (LMU Munich - application number 17-569) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent
Informed consent was obtained from all patients.

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