scholarly journals Quantitative Evaluation of 18F-Flutemetamol PET in Patients With Cognitive Impairment and Suspected Alzheimer's Disease: A Multicenter Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Hiroshi Matsuda ◽  
Kengo Ito ◽  
Kazunari Ishii ◽  
Eku Shimosegawa ◽  
Hidehiko Okazawa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Quantitative Analysis ◽  
Quantitative Evaluation ◽  
Standardized Uptake Value ◽  
Amyloid Pet ◽  
Visual Interpretation ◽  
Characteristic Analysis ◽  
Pet Scans

Background: In clinical practice, equivocal findings are inevitable in visual interpretation of whether amyloid positron emission tomography (PET) is positive or negative. It is therefore necessary to establish a more objective quantitative evaluation method for determining the indication for disease-modifying drugs currently under development.Aims: We aimed to determine cutoffs for positivity in quantitative analysis of 18F-flutemetamol PET in patients with cognitive impairment and suspected Alzheimer's disease (AD). We also evaluated the clinical efficacy of amyloid PET in the diagnosis of AD. This study was registered in the Japan Registry of Clinical Trials (jRCTs, 031180321).Methods: Ninety-three patients suspected of having AD underwent 18F-flutemetamol PET in seven institutions. A PET image for each patient was visually assessed and dichotomously rated as either amyloid-positive or amyloid-negative by two board-certified nuclear medicine physicians. If the two readers obtained different interpretations, the visual rating was rerun until they reached consensus. The PET images were quantitatively analyzed using the standardized uptake value ratio (SUVR) and standardized Centiloid (CL) scale with the whole cerebellum as a reference area.Results: Visual interpretation obtained 61 positive and 32 negative PET scans. Receiver operating characteristic analysis determined the best agreement of quantitative assessments and visual interpretation of PET scans to have an area under curve of 0.982 at an SUVR of 1.13 and a CL of 16. Using these cutoff values, there was high agreement between the two approaches (kappa = 0.88). Five discordant cases had SUVR and CL values ranging from 1.00 to 1.22 and from 1 to 26, respectively. In these discordant cases, either diffuse or mildly focal elevation of cortical activity confused visual interpretation. The amyloid PET outcome significantly altered the diagnosis of AD (χ2 = 51.3, p < 0.0001). PET imaging elevated the proportions of the very high likelihood category from 20.4 to 46.2% and the very low likelihood category from 0 to 22.6%.Conclusion: Quantitative analysis of amyloid PET using 18F-flutemetamol can objectively evaluate amyloid positivity using the determined cutoffs for SUVR and CL. Moreover, amyloid PET may have added value over the standard diagnostic workup in dementia patients with cognitive impairment and suspected AD.

scholarly journals Feasibility study of amyloid PET-only quantification; a comparison with visual interpretation.

2020 ◽  
Author(s):  
Natsumi Shimokawa ◽  
Go Akamatsu ◽  
Miyako Kadosaki ◽  
Masayuki Sasaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quantitative Evaluation ◽  
Quantitative Methods ◽  
Standardized Uptake Value ◽  
Amyloid Pet ◽  
Visual Interpretation ◽  
Visual Evaluation ◽  
Quantification Method ◽  
Sensitivity Specificity

Abstract Objective Visual evaluation is the standard for amyloid positron emission tomography (PET) examination, though the result depends upon the physician’s subjective review of the images. Therefore, objective quantitative evaluation is expected to be useful for image interpretation. In this study, we examined the usefulness of the quantitative evaluation of amyloid PET using a PET-only quantification method in comparison with visual evaluation. Methods A total of 166 individuals, including 58 cognitively normal controls, 62 individuals with mild cognitive impairment, and 46 individuals with early Alzheimer’s disease, were retrospectively investigated. They underwent 11C-Pittsburgh compound-B (PiB) PET examination through the Japanese-Alzheimer’s disease neuroimaging initiative (J-ADNI). Amyloid accumulation in cerebral cortices was assessed using visual and quantitative methods. The quantitative evaluation was performed using the adaptive template method and empirically PiB-prone region of interest, and the standardized uptake value ratio (SUVR) in each area was obtained. Results Visual evaluation and SUVR were significantly correlated in the cerebral cortices (ρ = 0.85–0.87; p < 0.05). In visual evaluation, the sensitivity, specificity, and accuracy were 78%, 76%, and 77%, respectively. Meanwhile, for quantitative evaluation, the sensitivity, specificity, and accuracy were 78%, 76%, and 77%, in mean cortical SUVR (mcSUVR) and 79%, 79%, and 79% in maximum SUVR (maxSUVR), respectively. Conclusion The PET-only quantification method resulted in a concordant result with visual evaluation and was considered to be useful for amyloid PET.

Elucidating the risk factors for progression from amyloid-negative amnestic mild cognitive impairment to dementia

2020 ◽  
Vol 17 ◽  
Author(s):  
Hyung-Ji Kim ◽  
Jae-Hong Lee ◽  
E-nae Cheong ◽  
Sung-Eun Chung ◽  
Sungyang Jo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amnestic Mild Cognitive Impairment ◽  
Amyloid Pet ◽  
Clinical Progression ◽  
Amnestic Mci

Background: Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer’s disease from Alzheimer’s disease-mimicking conditions. Around 15–20% of patients with clinically probable Alzheimer’s disease have been found to have no significant Alzheimer’s pathology on amyloid PET. However, a limited number of studies had been conducted this subpopulation in terms of clinical progression. Objective: We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI). Methods: This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloidnegative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET. Results: During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer’s disease-like pattern despite the lack of evidence for significant Alzheimer’s disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices. Conclusion: Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer’s diseasemimicking dementia are warranted.

scholarly journals Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer’s Disease and Other Dementias

2020 ◽  
pp. 1-14
Author(s):  
Yi-Wen Bao ◽  
Anson C.M. Chau ◽  
Patrick Ka-Chun Chiu ◽  
Yat Fung Shea ◽  
Joseph S.K. Kwan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Subjective Cognitive Decline ◽  
Cognitively Impaired ◽  
Memory Clinic ◽  
Pet Ct

Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.

scholarly journals Identification of and a Prediction Model for Cognitive Trajectories in Patients With Mild Cognitive Impairment Due to Alzheimer’s Disease

2020 ◽  
Author(s):  
Sang Won Seo ◽  
Seung Joo Kim ◽  
Sook-Young Woo ◽  
Young Ju Kim ◽  
Yeshin Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Prediction Model ◽  
Multinomial Logistic Regression ◽  
Standardized Uptake Value ◽  
Disease Assessment ◽  
Risk Scores ◽  
Clinical Biomarkers

Abstract Background: Few studies have investigated cognitive trajectories or developed a prediction model for amyloid beta-positive (Aβ+) mild cognitive impairment (MCI) patients. We aimed to identify distinct cognitive trajectories in Aβ+ MCI patients based on longitudinal Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog) 13 scores. Furthermore, we aimed to develop and visualize a prediction model to predict trajectory groups using the demographic, genetic, and clinical biomarkers of Aβ+ MCI patients.Methods: We performed a retrospective analysis of the data in 238 Aβ+ MCI patients from the Alzheimer’s Disease Neuroimaging Initiative who underwent at least three rounds of annual neuropsychological testing to identify cognitive trajectories. A group-based trajectory model (GBTM) was used to classify distinct groups based on ADAS-cog 13 scores. The prediction model was estimated using multinomial logistic regression and visualized using a bar-based method for risk prediction. Results: Three distinct classes, namely slow decliners (18.5%), intermediate decliners (42.9%), and fast decliners (38.7%), were suggested. Intermediate decliners were associated with higher age (≥70 years) (odds ratio [OR] 2.72, 95% confidence interval [CI] 1.78-6.28), higher AV45 standardized uptake value ratios (SUVRs)*10 (OR 1.69, 95% CI 1.22-2.34), and lower fluorodeoxyglucose (FDG) SUVR*10 (OR 0.65, 95% CI 0.46-0.93) than slow decliners. Fast decliners were associated with higher age (≥70 years) (OR 3.76, 95% CI 1.40-10.10), greater likelihood of being an apolipoprotein E 4 carrier (OR 4.2, 95% CI 1.53-11.58), higher AV45 positron emission tomography SUVR*10 (OR 2.14, 95% CI 1.50-3.05), and lower FDG SUVR*10 (OR 0.31, 95% CI 0.20-0.48) than slow decliners. The predicted probability of being classified to a trajectory group according to the risk scores of predictors was visualized.Conclusions: Our GBTM analysis yielded novel insights into the heterogeneous cognitive trajectories among Aβ+ MCI patients, which further facilitates the effective stratification of Aβ+ MCI patients in Aβ-targeted clinical trials.

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

Brain ◽  
2020 ◽  
Vol 143 (9) ◽  
pp. 2818-2830 ◽  
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 &lt; 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 &lt; 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.

scholarly journals Effect of APOE ε4 genotype on amyloid-β and tau accumulation in Alzheimer’s disease

2020 ◽  
Author(s):  
Min Seok Baek ◽  
Hanna Cho ◽  
Hye Sun Lee ◽  
Jae Hoon Lee ◽  
Young Hoon Ryu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Accumulation Rate ◽  
Temporal Cortex ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Linear Mixed Effect Model ◽  
Mixed Effect ◽  
Apoe Ε4 ◽  
Pet Scans

Abstract Background: To assess effects of apolipoprotein E (ApoE) ε4 genotype on Aβ and tau burden and their longitudinal changes in Alzheimer’s disease (AD) spectrum.Methods: Among 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for partial-volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4- groups.Results: The ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.Conclusions: Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on Aβ burden depending on the existing amyloidosis and enhances vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

scholarly journals Repeatability of parametric methods for [18F]florbetapir imaging in Alzheimer’s disease and healthy controls: A test–retest study

2020 ◽  
pp. 0271678X2091540 ◽  
Author(s):  
Sander CJ Verfaillie ◽  
Sandeep SV Golla ◽  
Tessa Timmers ◽  
Hayel Tuncel ◽  
Chris WJ van der Weijden ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Standardized Uptake Value ◽  
Emission Tomography ◽  
Parametric Methods ◽  
Excellent Performance ◽  
Reference Tissue ◽  
Positron Emission ◽  
Arterial Sampling ◽  
Pet Scans

Accumulation of amyloid beta (Aβ) is one of the pathological hallmarks of Alzheimer’s disease (AD), which can be visualized using [18F]florbetapir positron emission tomography (PET). The aim of this study was to evaluate various parametric methods and to assess their test-retest (TRT) reliability. Two 90 min dynamic [18F]florbetapir PET scans, including arterial sampling, were acquired ( n = 8 AD patient, n = 8 controls). The following parametric methods were used; (reference:cerebellum); Logan and spectral analysis (SA), receptor parametric mapping (RPM), simplified reference tissue model2 (SRTM2), reference Logan (rLogan) and standardized uptake value ratios (SUVr(50–70)). BPND+1, DVR, VT and SUVr were compared with corresponding estimates (VT or DVR) from the plasma input reversible two tissue compartmental (2T4k_VB) model with corresponding TRT values for 90-scan duration. RPM ( r2 = 0.92; slope = 0.91), Logan ( r2 = 0.95; slope = 0.84) and rLogan ( r2 = 0.94; slope = 0.88), and SRTM2 ( r2 = 0.91; slope = 0.83), SA ( r2 = 0.91; slope = 0.88), SUVr ( r2 = 0.84; slope = 1.16) correlated well with their 2T4k_VB counterparts. RPM (controls: 1%, AD: 3%), rLogan (controls: 1%, AD: 3%) and SUVr(50–70) (controls: 3%, AD: 8%) showed an excellent TRT reliability. In conclusion, most parametric methods showed excellent performance for [18F]florbetapir, but RPM and rLogan seem the methods of choice, combining the highest accuracy and best TRT reliability.

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