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

Abstract

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.

Assessment of perfusion deficit with early phases of [18F]PI-2620 tau-PET versus [18F]flutemetamol-amyloid-PET recordings

“…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 [25]. Thus, perfusionweighted imaging with [ 18 F]flutemetamol or [ 18 F]PI-2620 can serve for monitoring disease severity, irrespective of their properties as molecular imaging agents with specific for amyloid-β or tau.…”

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

“…Patients with 4-repeat tauopathies similarly showed a signi cant 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 de cit and the PSP rating scale scores in patients with 4R-tauopathies [22]. Thus, perfusion-weighted imaging with [ 18 F] utemetamol or [ 18 F]PI-2620 can serve for monitoring disease severity, irrespective of their properties as molecular imaging agents with speci c for β-amyloid or tau.…”

“…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].…”

Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies

“…From the dynamic PET image acquisition, we reconstructed late-phase tau-PET images for 20-40 min p.i. which were summarized into a single frame after motion correction (30,(40)(41)(42).…”