The imaging features and clinical associations of a novel tau PET tracer - 18F-APN1607(18F-PM-PBB3) in Alzheimer’s disease

Abstract Background: In vivo tau positron emission tomography (PET) imaging could help clarify the spatial distribution of tau deposition in Alzheimer’s disease (AD) and aid in the differential diagnosis of tauopathies. To date, there have been no in vivo 18 F-APN1607 tau PET studies in patients with AD.Methods: We applied tau tracer in twelve normal controls (NCs) and ten patients in the mild to moderate stage of probable AD. Detailed clinical information, cognitive measurements and disease severity were documented. Regional standardized uptake value ratios (SUVRs) from 18 F-AV-45 (florbetapir), 18 F-APN1607 PET images and regional gray matter (GM) atrophic ratios were calculated for further analysis.Results: Quantitative analyses showed significantly elevated SUVRs in the frontal, temporal, parietal, occipital lobes, anterior and posterior cingulate gyri, precuneus, and parahippocampal region (all ps < 0.01) with medium to large effect sizes (0.44 - 0.75). The SUVRs from 18 F-APN1607 PET imaging showed significant correlations with the ADAS-cog scores (all ps < 0.01) and strong correlation coefficients (R squared ranged from 0.54 to 0.68), even adjusted for age and gender effects. Finally, the SUVRs from 18 F-APN1607 PET imaging of the parahippocampal region showed rapid saturation as the ADAS-cog scores increased, and the SUVRs of the posterior cingulate gyrus and the temporal, frontal, parietal and occipital regions slowly increased. The combined SUVRs from 18 F-AV-45 PET, 18 F-APN1607 PET and regional GM atrophic ratio showed that uptake associated with the amyloid burden rapidly increased and reach a plateau, whereas uptake associated with tau depositions increased slowly and finally followed by regional GM atrophic ratios in most regions as the ADAS-cog scores increased. However, different regions exhibited various combinations of these patterns.Conclusions: Our findings suggest that the 18 F-APN1607 tau tracer showed a clear background without significant uptake in the basal ganglia or midbrain. Uptake of this tracer correlated well with cognitive changes and demonstrated the spatial pattern of amyloid, tau deposition and GM atrophy in the progression of AD. Thus, the regional base of dynamic biomarker changes was observed in the current study.Trial registration: registration number (NCT03625128), date of registration( August 10, 2018), retrospectively registered.

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[P3-338]: IN VIVO TAU PET IMAGING IN EARLY-ONSET ALZHEIMER's DISEASE AND LATE-ONSET ALZHEIMER's DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1553 ◽

2017 ◽

Vol 13 (7S_Part_22) ◽

pp. P1083-P1083

Author(s):

Young Noh ◽

Han Kyu Na ◽

Seongho Seo ◽

Sang-Yoon Lee ◽

Hye Jin Jeong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Early Onset ◽

Late Onset ◽

Early Onset Alzheimer’S Disease ◽

Tau Pet ◽

Tau Pet Imaging

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Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies

Brain Communications ◽

10.1093/braincomms/fcab190 ◽

2021 ◽

Vol 3 (4) ◽

Cited By ~ 1

Author(s):

Toshiki Tezuka ◽

Keisuke Takahata ◽

Morinobu Seki ◽

Hajime Tabuchi ◽

Yuki Momota ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Progressive Supranuclear Palsy ◽

Standardized Uptake Value ◽

Corticobasal Degeneration ◽

Post Injection ◽

Healthy Controls ◽

Tau Pathology ◽

Tau Pet

Abstract Tau aggregates represent a key pathologic feature of Alzheimer’s disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer’s disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer’s disease tauopathies compared with Alzheimer’s disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer’s disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [18F]PI-2620 PET (Image acquisition at 60–90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer’s disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer’s disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer’s disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer’s disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60–90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer’s disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer’s disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer’s disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer’s disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

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In vivo characterization and quantification of neurofibrillary tau PET radioligand [18F]MK-6240 in humans from Alzheimer’s disease dementia to young controls

10.1101/290064 ◽

2018 ◽

Cited By ~ 3

Author(s):

Tobey J Betthauser ◽

Karly A Cody ◽

Matthew D Zammit ◽

Dhanabalan Murali ◽

Alexander K Converse ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Optimal Timing ◽

Reference Tissue ◽

Time Activity ◽

Imaging Characteristics ◽

Tau Pet ◽

Target Binding

ABSTRACTTau positron emission tomography (PET) imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer’s disease (AD). This work investigatesin vivokinetics, quantification strategies and imaging characteristics of a novel tau PET radioligand [18F]MK-6240 in humans.MethodsFifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted magnetic resonance imaging (MRI), and [11C]PiB and [18F]MK-6240 PET imaging. PET data were coregistered to the MRI and time-activity curves were extracted from regions of interest to assess [18F]MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis (LGA) and multilinear reference tissue method (MRTM2)) were investigated for quantification of [18F]MK-6240 distribution volume ratios (DVRs) in a subset of nineteen participants. Stability of DVR methods was evaluated using truncated scan durations. Standard uptake value ratio (SUVR) estimates were compared to DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature.ResultsStandard uptake values in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared to MRTM2. DVR estimates remained stable when truncating the scan duration to 60 minutes. SUVR determined 70-90 minutes post-injection of [18F]MK-6240 indicated linearity near unity when compared to DVR estimates and minimized potential spill-in from uptake outside of the brain. [18F]MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus.Conclusions[18F]MK-6240 is a promising PET radioligand forin vivoimaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.

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Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia

Molecular Psychiatry ◽

10.1038/mp.2017.108 ◽

2017 ◽

Vol 23 (7) ◽

pp. 1666-1673 ◽

Cited By ~ 48

Author(s):

K Chiotis ◽

L Saint-Aubert ◽

E Rodriguez-Vieitez ◽

A Leuzy ◽

O Almkvist ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Longitudinal Changes ◽

Tau Pet ◽

Alzheimer’S Disease Dementia ◽

Tau Pet Imaging

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O1-07-06: Hippocampal sparing and limbic predominant tau subtypes of Alzheimer's disease determined in vivo using [18F]-AV-1451 PET imaging

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.07.068 ◽

2015 ◽

Vol 11 (7S_Part_3) ◽

pp. P144-P145 ◽

Cited By ~ 1

Author(s):

Adam J. Schwarz ◽

Sergey Shcherbinin ◽

Bradley B. Miller ◽

Peng Yu ◽

Michael Navitsky ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Hippocampal Sparing

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Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET

Science Translational Medicine ◽

10.1126/scitranslmed.aau5732 ◽

2020 ◽

Vol 12 (524) ◽

pp. eaau5732 ◽

Cited By ~ 49

Author(s):

Renaud La Joie ◽

Adrienne V. Visani ◽

Suzanne L. Baker ◽

Jesse A. Brown ◽

Viktoriya Bourakova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Specific Distribution ◽

Positron Emission ◽

Pet Radiotracers ◽

Β Amyloid ◽

Tau Pet ◽

Prospective Longitudinal

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.

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P4-315: TAU PET IMAGING WITH 18 F-PI2620 IN AGING AND ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.07.138 ◽

2006 ◽

Vol 14 (7S_Part_30) ◽

pp. P1577-P1578

Author(s):

Elizabeth C. Mormino ◽

Ayesha Nadiadwala ◽

Carmen Azevedo ◽

Wanjia Guo ◽

Jessa B. Castillo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pet Imaging ◽

Tau Pet ◽

Tau Pet Imaging

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18F-MK-6240 PET for early and late detection of neurofibrillary tangles

Brain ◽

10.1093/brain/awaa180 ◽

2020 ◽

Vol 143 (9) ◽

pp. 2818-2830 ◽

Cited By ~ 6

Author(s):

Tharick A Pascoal ◽

Joseph Therriault ◽

Andrea L Benedet ◽

Melissa Savard ◽

Firoza Z Lussier ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Standardized Uptake Value ◽

Braak Staging ◽

High Affinity ◽

Tau Pet ◽

Transentorhinal Cortex

Abstract Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer’s disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I–II), in contrast to ∼80–90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer’s disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90–110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer’s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85–100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV–VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V–VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer’s disease in the near future.

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