Tessa Timmers

Purpose: To assess the clinical value of [ ¹⁸ F]fluoroethyl-L-tyrosine PET ([ ¹⁸ F]FET-PET) correlated with MRI in patients with functioning pituitary adenoma (FPA) with negative or equivocal conventional MRIs during diagnosis, persistent disease and recurrence. Methods: Retrospective observational cohort study of 34 patients with FPAs who underwent a total of 37 [ ¹⁸ F]FET-PETs (Cushing’s disease: n = 19, acromegaly: n = 14, prolactinoma: n = 3, and TSH producing adenoma: n = 1) between January 2022 and April 2025. The clinical performance was assessed in the surgically treated cohort, using confirmative histopathology and/or postoperative remission as reference standard. Results: [ ¹⁸ F]FET-PET identified a single lesion in 28 scans (76%), two lesions in 1 scan (3%), and no lesion in 8 scans (22%). [ ¹⁸ F]FET-PET and MRI were concordant positive in 14/37 scans, concordant negative in 1/37, discordant MRI+/[ ¹⁸ F]FET-PET + different location in 2/37, discordant MRI-/[ ¹⁸ F]FET-PET + in 8/37, discordant MRI+/[ ¹⁸ F]FET-PET- in 7/37 and partly concordant in 5/37 scans. In 14 cases surgery resulted in confirmative histopathology and/or postoperative remission, 12 of those had a positive [ ¹⁸ F]FET-PET. In 6 cases surgery did not result in confirmative histopathology and/or postoperative remission, of whom 5 had a positive [ ¹⁸ F]FET-PET. Overall, the sensitivity was 86% and the positive predictive value 71%. In three patients with acromegaly, [ ¹⁸ F]FET-PET was able to localize a lesion, despite biochemical control under continued somatostatin analogue treatment. Conclusion: [ ¹⁸ F]FET-PET enhances lesion detection and improves personalized treatment in patients with FPA and negative or equivocal conventional MRIs throughout the disease course. Consensus on the timing of [ ¹⁸ F]FET-PET with respect to medication and biochemical status is warranted.

Background: Several studies validated R₁ as a marker for relative cerebral blood flow (rCBF). However, the similarities or differences of R₁ estimates obtained from different PET tracers has never been investigated.Aim: The aim of the current study was head‐to‐head comparison of R₁ estimates, derived from dynamic [¹⁸F]florbetapir and [¹⁸F]flortaucipir PET scans.Method: Fifty subjects with subjective cognitive decline (Aβ‐;N = 31, Aβ+;N = 19) underwent both [¹⁸F]florbetapir and [¹⁸F]flortaucipir PET (interval: 50.6 ± 34.7 days). Receptor parametric mapping (RPM) was used to generate R₁ maps with cerebellar grey matter as reference. For voxel‐wise analyses, Statistical Parametric Mapping software (SPM12) was used. Furthermore, different regions‐of‐interest were assessed (in subject‐space). Paired t‐tests, coefficients of determination (r²) and ICC were used to compare R₁ estimates from [¹⁸F]florbetapir and [¹⁸F]flortaucipir PET.Results: Voxel‐wise analysis revealed only a few small significant clusters in part of the thalamus, insular gyri, midbrain and part of the cerebellum with higher R₁ estimates for [¹⁸F]florbetapir and higher R₁ estimates in the hippocampus, vermis, midbrain and calcarine sulcus for [¹⁸F]flortaucipir in Aβ‐ subjects (Figure 1a & 1b). In Aβ+ subjects, [¹⁸F]florbetapir showed higher R₁ estimates only in part of the thalamus and [¹⁸F]flortaucipir showed higher R₁ estimates in the hippocampus and striatum (Figure 1c & 1d). Despite the small amount of significant voxels, [¹⁸F]florbetapir R₁ showed good correlation and excellent ICC with [¹⁸F]flortaucipir for whole brain (Aβ‐:r² = 0.76, ICC:0.92; Aβ+:r² = 0.60,ICC = 0.87).Conclusion: To conclude, [¹⁸F]flortaucipir and [¹⁸F]florbetapir showed similar R₁ estimates in cortical regions, illustrating that R₁ is a robust marker for flow independent of tracer of interest.

Objective To assess the [¹⁸F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers. Methods We compared regional [¹⁸F]flortaucipir binding potential (BP_ND) derived from a 130-minute dynamic [¹⁸F]flortaucipir PET scan in 9 (pre)symptomatic MAPT mutation carriers (4 with P301L [1 symptomatic], 2 with R406W [1 symptomatic], 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease. Results [¹⁸F]Flortaucipir BP_ND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BP_ND was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated [¹⁸F]flortaucipir BP_ND in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BP_ND, with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BP_ND compared to controls. The BP_ND values of the S320F presymptomatic mutation carrier fell within the range of controls. Conclusion Presymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [¹⁸F]flortaucipir BP_ND. Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [¹⁸F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies.

Purpose: Semi-quantitative PET measures can be affected by changes in blood flow, whereas quantitative measures are not. The aim of the study was to compare semi-quantitative(SUVr) and quantitative(R ₁ , BP _ND ) parameters of longitudinal tau PET scans with [ ¹⁸ F]flortaucipir, with respect to changes in blood flow. Methods: Subjects with subjective cognitive decline(SCD; n=38) and Alzheimer’s disease(AD) patients(n=24) underwent baseline(BL) and 2-year follow-up(FU) dynamic [ ¹⁸ F]flortaucipir PET scans. BP _ND and R ₁ were estimated using RPM and SUVr _(80-100min) was calculated (cerebellar gray as reference). For each region-of-interest ((trans)entorhinal, limbic and neocortical) and parameter, %change was calculated. Regional SUVrs were compared to corresponding DVR (= BP _ND +1) using paired T-tests. Additionally, simulations were performed to model effects of flow changes on BP _ND and SUVr in different binding categories. Thereafter, %bias for SUVr with respect to underlying binding and flow were evaluated. Results: In SCD, there was a difference between %change in the (trans)entorhinal ROI (DVR 2.56% vs SUVr 1.85%) only. In AD, a difference was found in the limbic ROI (DVR 6.61% vs SUVr 7.52%) only. R ₁ changes were small(+0.7% in SCD and -1.6% in AD). Simulations illustrated with increasing flow a decreased %bias for SUVr in low binding conditions, whereas a slightly increased bias was observed in high binding conditions. Conclusion: SUVr provided an accurate estimate of specific binding for [ ¹⁸ F]flortaucipir over a two-year follow-up. However, simulations showed that flow changes can affect [ ¹⁸ F]flortaucipir SUVr, hence DVR/BP _ND should be preferred in more advanced disease stages and/or conditions that could induce significant flow changes like pharmacotherapeutic interventions.

Purpose: Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [ ¹⁸ F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. Methods: Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n=35, age-at-PET=59±5, MMSE=23±4; LOAD: n=44, age-at-PET=71±5, MMSE=23±4) underwent a 130 minutes dynamic [ ¹⁸ F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BP _ND ) and R ₁ (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language and executive functioning. We first examined differences between EOAD and LOAD in BP _ND or R ₁ using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BP _ND /R ₁ on cognition. Results: Both region-of-interest and voxel-wise contrasts showed higher [ ¹⁸ F]flortaucipir BP _ND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R ₁ values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipito-parietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BP _ND -0.76≤stβ≤-0.48 vs LOAD -0.18≤stβ≤-0.02; EOAD R ₁ 0.37≤stβ≤0.84 vs LOAD -0.25≤stβ≤0.16). Conclusions: Compared to LOAD, the degree of lateral temporal and occipito-parietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.

The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for [¹⁸F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic [¹⁸F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr_80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr_80–100 and SUVr_110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.

Neuropathological studies have linked tau aggregates to neuronal loss. To describe the spatial distribution of neurofibrillary tangle pathology in post-mortem tissue, Braak staging has been used. The aim of this study was to examine in vivo associations between tau pathology, quantified with [18F]flortaucipir PET in regions corresponding to Braak stages, and atrophy across the Alzheimer’s disease (AD) spectrum. We included 100 subjects, including 58 amyloid-β positive patients with mild cognitive impairment (MCI, n = 6) or AD dementia (n = 52) and 42 controls with subjective cognitive decline (36% amyloid-β positive). All subjects underwent a dynamic [18F]flortaucipir PET to generate non-displaceable binding potential (BPND) maps. We extracted average [18F]flortaucipir BPND entorhinal, Braak III–IV (limbic) and Braak V–VI (neocortical) regions of interest (ROIs). T1-weighted MRI was used to assess gray matter (GM) volumes. We performed linear regression analyses using [18F]flortaucipir BPND ROIs as independent and GM density (ROI or voxelwise) as dependent variable. In MCI/AD subjects (age [mean ± SD] 65 ± 8 years, MMSE 23 ± 4), [18F]flortaucipir BPND was higher than in controls (age 65 ± 8, MMSE 29 ± 1) across all ROIs (entorhinal 0.06 ± 0.21 vs 0.46 ± 0.25 p < 0.001, Braak III–IV 0.11 ± 0.10 vs 0.46 ± 0.26, p < 0.001, Braak V–VI 0.07 ± 0.07 vs 0.38 ± 0.29, p < 0.001). In MCI/AD, greater [18F]flortaucipir BPND in entorhinal cortex was associated with lower GM density in medial temporal lobe (β − 0.40, p < 0.001). Greater [18F]flortaucipir BPND in ROI Braak III–IV and Braak V–VI was associated with smaller GM density in lateral and inferior temporal, parietal, occipital, and frontal lobes (range standardized βs − 0.30 to − 0.55, p < 0.01), but not in medial temporal lobe (β − 0.22, p 0.07). [18F]Flortaucipir BPND in ROI Braak I–II was not associated with GM density loss anywhere. When quantifying [18F]flortaucipir BPND across brain lobes, we observed both local and distant associations with GM atrophy. In controls, there were no significant associations between [18F]flortaucipir BPND and GM density (standardized βs ranging from − 0.24 to 0.02, all p > 0.05). In MCI/AD patients, [18F]flortaucipir binding in entorhinal, limbic, and neocortical regions was associated with cortical atrophy.

Off-target binding in the choroid plexus (CP) may cause spill-in of the tau PET tracer [18F] flortaucipir into the adjacent hippocampus region. The impact of this spill-in on hippocampal uptake was assessed using a novel partial volume correction method (PVC). PVC was performed on 20 [18F] flortaucipir dynamic PET scans (10 probable AD and 10 controls). Volumes of interest (VOIs) were defined for both hippocampus and CP. The correlation between hippocampal and CP distribution volume (VT), with and without PVC, was determined. Both anatomically defined and eroded VOIs were used. For controls, the correlation between hippocampal and CP VT was significantly reduced after using PVC along with an eroded VOI (r2 = 0.59, slope = 0.80 versus r2 = 0.15, slope = 0.15; difference: p < 0.05). The same was true for AD patients (p < 0.05). PVC together with an optimized hippocampal VOI resulted in effective reduction of CP spill-in and improved accuracy of hippocampal VT.

Alzheimer’s disease is a neurodegenerative condition that is neuropathologically characterized by the presence of amyloid-β plaques and neurofibrillary tangles consisting of tau. Recently, several positron emission tomography (PET) tracers have been developed that yielded promising initial results. In this chapter, we discuss how tau PET can be used in the context in clinical trials. We argue that simplified reference tissue models based on dynamic data acquisition are most suitable for accurately measuring changes in tau pathology in trials tailored to reduce cerebral tau load. Therefore, we discuss the importance of tracer kinetic modeling and describe in detail how a reliable measurement of specific binding can be obtained.