Dual-Phase β-Amyloid PET Captures Neuronal Injury and Amyloidosis in Corticobasal Syndrome

Schmitt, Julia; Palleis, Carla; Sauerbeck, Julia; Harris, Stefanie; Prix, Catharina; Weidinger, Endy; Katzdobler, Sabrina; Wagemann, Olivia; Danek, Adrian; Beyer, Leonie; Rauchmann, Boris‐Stephan; Rominger, Axel; Simons, Mikael; Bartenstein, Peter; Perneczky, Robert; Haass, Christian; Levin, Johannes; Höglinger, Günter U.; Brendel, Matthias

doi:10.3389/fnagi.2021.661284

Cited by 16 publications

(34 citation statements)

References 37 publications

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“…We selected 0.5-2.5 min SUVr since this methodology can be achieved by a simple dual-phase [ 18 F]PI-2620 protocol, readily providing images for clinical interpretation without high sophisticated reconstruction and analysis methodology. In line with the known patterns of neuronal injury that were detected by perfusion imaging or FDG-PET in 4RTs [6, [19][20][21], we found a fronto-temporal and subcortical hypoperfusion with predominance in the thalamus, the caudate nucleus and the anterior cingulate cortex at the group level of 4RTs against healthy controls. The putamen and the globus pallidus indicated a non-signi cant hyperperfusion, which was consistent with the regionally elevated time-activity-curves in the basal ganglia of patients with PSP within the perfusion phase [1].…”

Section: Discussionsupporting

confidence: 89%

Additive value of [18F]PI-2620 perfusion imaging in four-repeat tauopathies

Katzdobler¹,

Nitschmann²,

Barthel

et al. 2022

Preprint

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Purpose Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate 4-repeat tauopathies (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. Methods Seventy-eight patients with 4RTs (71±7y, 39 female), 79 patients with other neurodegenerative diseases (67±12y, 35 female) and twelve age-matched controls (69±8y, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value-ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p<0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value-2SD threshold). Additionally, perfusion and tau pattern expression levels were tested for discrimination of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n=37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). Results Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression discriminated patients with 4RTs well from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was validated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = -0.431; p = 0.0005). Conclusion [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression provides an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

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Section: Discussionsupporting

confidence: 89%

Additive value of [18F]PI-2620 perfusion imaging in four-repeat tauopathies

Katzdobler¹,

Nitschmann²,

Barthel

et al. 2022

Preprint

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“…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 ndings 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].…”

Section: Discussionsupporting

confidence: 93%

“…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][14][15]22].…”

Section: Resultsmentioning

confidence: 99%

“…for [ 18 F] utemetamol-PET and 0.5-2.5 min p.i. for [ 18 F]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).…”

Section: Image Processing and Analysismentioning

confidence: 99%

“…For each scan, we obtained segmentation of the SUV maps for each of the 246 brain regions de ned 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.…”

Section: Image Processing and Analysismentioning

confidence: 99%

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

Völter

Beyer

Eckenweber

et al. 2022

Preprint

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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.

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Microglial Activation and Connectivity in Alzheimer Disease and Aging

Rauchmann

Brendel

Franzmeier

et al. 2022

Annals of Neurology

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Objective: Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. Methods: We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [ 18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. Results: We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker

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Dual-Phase β-Amyloid PET Captures Neuronal Injury and Amyloidosis in Corticobasal Syndrome

Cited by 16 publications

References 37 publications

Additive value of [18F]PI-2620 perfusion imaging in four-repeat tauopathies

Additive value of [18F]PI-2620 perfusion imaging in four-repeat tauopathies

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

Microglial Activation and Connectivity in Alzheimer Disease and Aging

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