Standardized Uptake Value Ratio Values Research Articles

Could tau-PET imaging contribute to a better understanding of the different patterns of clinical progression in Alzheimer’s disease? A 2-year longitudinal study

BackgroundMonitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer’s disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [18F]-flortaucipir binding and of cortical atrophy, and their relationships with cognitive decline.MethodsTwenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [18F]-flortaucipir PET imaging (Tau1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline.ResultsWe found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression.ConclusionsDespite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with a potentially “more aggressive” clinical course characterized by high temporoparietal Tau1 SUVr values and a rapid clinical progression. In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.

Clinical outcomes of increased focal amyloid uptake in individuals with subthreshold global amyloid levels.

Although the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased β-amyloid (Aβ) uptake and global Aβ status. We recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach. A total of 62 (6.4%) subjects showed increased focal Aβ uptake with subthreshold global Aβ status [global (-) and focal (+) Aβ group, G(-)F(+) group]. The G(-)F(+) group showed worse performance in memory impairment (p < 0.001), global cognition (p = 0.009), greater hippocampal atrophy (p = 0.045), compared to those in the G(-)F(-). Participants with widespread Aβ involvement in the whole region [G(+)] showed worse neuropsychological (p < 0.001) and neuroimaging features (p < 0.001) than those with focal Aβ involvement G(-)F(+). Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aβ uptake and global Aβ status. Thus, researchers and clinicians should pay more attention to focal increased Aβ uptake in addition to global Aβ status.

Plasma Oligomer β-Amyloid and White Matter Microstructural Integrity in Cognitively Normal Older Adults According to Cerebral Amyloid Deposition.

Multimer detection system-oligomeric amyloid-β (MDS-OAβ) measure plasma OAβ level, which is associated with earlier Alzheimer's disease (AD) pathology. However, no study has investigated MDS-OAβ differences in cognitive normal older adults (CN) with or without cerebral Aβ burden and its correlation with Aβ deposition and white matter (WM) integrity. To investigate associations among cerebral Aβ burden, MDS-OAβ, and WM integrity in CN. This is a single center, cross-sectional study which used data from Catholic Aging Brain Imaging (CABI) database. CABI database contains brain scans of patients who visited the outpatient clinic at Catholic Brain Health Center, Yeouido St. Mary's Hospital, The Catholic University of Korea, between 2017 and 2022. A total 34 amyloid-PET negative CN and 23 amyloid-PET positive CN were included. Plasma Aβ level using MDS-OAβ, cerebral Aβ deposition level using global standardized uptake value ratio (SUVR) values, WM integrity using fractional anisotropy (FA) and mean diffusivity (MD), and cortical thickness from structural MRI were utilized. The amyloid-PET positive group showed higher MDS-OAβ level than the amyloid-PET negative group (0.997 ± 0.19 vs. 0.79 ± 0.28, P <0.005), but they did not differ in WM integrity or cortical thickness. The MDS-OAβ positive group showed higher global cerebral Aβ deposition or mean global SUVR values (0.609 ± 0.135 vs. 0.533 ± 0.121 vs. P <0.05), lower regional FA of left forceps minor and the right superior longitudinal fasciculus (family-wise error rate, p <0.05), and lower cortical thickness of left fusiform (p <0.05, Monte Carlo simulation) than the MDS-OAβ negative group. MDS-OAβ was positively associated with global cerebral Aβ deposition (r=0.278, P <0.05) and negatively associated (r = - 0.324, P < 0.05) with regional WM integrity. In this study, MDS-OAβ value demonstrated earlier and different AD pathology than cerebral Aβ retention according to amyloid-PET. Longitudinal studies are needed to elucidate the causal relationships of plasma OAβ and cerebral Aβ with WM integrity disturbance and cortical atrophy during the AD trajectory.

Correlation Between Neuromelanin-Sensitive MRI and 18F-FP-CIT PET in Early-Stage Parkinson's Disease: Utility of a Voxel-Wise Analysis by Using High-Spatial-Resolution MRI.

The correlation between dopamine transporter (DAT) imaging and neuromelanin-sensitive magnetic resonance imaging (NM-MRI) in early-stage Parkinson's disease (PD) has not yet been established. This study aimed to determine the correlation between NM-MRI and DAT positron-emission tomography (PET) in patients with early-stage PD. Fifty drug-naïve patients with early-stage PD who underwent both 0.8-mm isovoxel NM-MRI and DAT PET were enrolled retrospectively. Using four regions of interest (nigrosome 1 and nigrosome 2 [N1 and N2] regions) from a previous study, the contrast ratios (CRs) of 12 regions were measured: N1, N2, flipped N1, flipped N2, combined N1 and N2, and whole substantia nigra pars compacta [SNpc] (all on both sides). The clinically more affected side was separately assessed. The standardized uptake value ratios (SUVRs) were measured in the striatum using DAT PET. A partial correlation analysis was performed between the SUVR and CR measurements. CR of the flipped left N1 region was significantly correlated with SUVR of the right posterior putamen (p=0.047), and CR values of the left N1 region, left N2 region, flipped right N1 region, and combined left N1 and N2 regions were significantly correlated with SUVR of the left posterior putamen (p=0.011, 0.038, 0.020, and 0.010, respectively). SUVR of the left anterior putamen was significantly correlated with CR of the left N2 region (p=0.027). On the clinically more affected side, the CR values of the N1 region, combined N1 and N2 regions, and the whole SNpc were significantly correlated with SUVR of the posterior putamen (p=0.001, 0.024, and 0.021, respectively). There were significant correlations between the SUVR of the anterior putamen and the CR values of the N1 region, combined N1 and N2 regions, and whole SNpc (p=0.027, 0.001, and 0.036, respectively). This study found that there were significant correlations between CR values in the SNpc on NM-MRI and striatal SUVR values on DAT PET on both sides in early-stage PD.

Composite SUVR: a new method for boosting Alzheimer’s disease monitoring and diagnostic performance, applied to tau PET

AbstractBackgroundAbnormal brain tau protein accumulation is strongly linked to multiple neurodegenerative disorders. Currently, brain tau pathology is quantified in vivo using tau PET by calculating the Standardized Uptake Value Ratio (SUVR) of target and reference regions of interest (ROIs).Recent work (Schwarz et al., 2021) in Alzheimer’s Disease (AD) explored various target and reference ROIs to report performance of SUVR as a biomarker for diagnosis, disease monitoring, and clinical trial efficacy/eligibility (sample size estimate, SSE). Here we introduce a new method and biomarker: Composite SUVR (CUVR).MethodsWe analyzed longitudinal SUV data from ADNI in the available 103 participants having three or more tau PET scans ([18F]AV‐1451): 58 cognitively normal (CN); 21 mild cognitive impairment; 24 probable AD. In the spirit of SUVR and statistical ROIs (Chen, et al., NeuroImage 2010), we calculate CUVR as the SUV ratio of two composite regions. Our novel method is that the composite regions are determined by a genetic algorithm that searches the possible 3^96 combinations of regions from FreeSurfer’s default atlas. We compare performance of SUVR with CUVR.Performance metrics follow Schwarz et al.: a linear mixed‐effects model quantifies longitudinal group separation by tau accumulation rate (t statistic between fixed effects for CN and AD) and longitudinal precision (model residuals’ standard deviation). CUVR and SUVR values were log‐transformed before model fitting.We calculated SSE for a hypothetical clinical trial designed for 80% power to reduce tau PET accumulation by 20% (vs. placebo) in non‐CN individuals.ResultsOur method identified a CUVR biomarker involving 60 regions. Figure‐1 shows the vast performance improvement of CUVR versus the best‐performing SUVR (inferior‐temporal target; eroded subcortical white matter reference). Group separation improved by 2.9x (t = 9.57 vs 3.32); longitudinal precision by 6.5x (residual std = 0.331% vs 2.14%); and CUVR required a smaller sample size by 3.9x (83 vs 318).ConclusionsOur simple data‐driven approach discovered a new tau PET biomarker called CUVR. Experimental results show state‐of‐the‐art longitudinal group separation, longitudinal precision, and clinical trial enrichment. The remarkable performance improvements provide compelling evidence for using CUVR for both eligibility and efficacy in Alzheimer’s disease clinical trials, particularly of anti‐tau therapies.

In vivo cholinergic system integrity and cognition using [18F]‐FEOBV PET in healthy postmenopausal women: a pilot study

AbstractBackgroundWomen are at a higher risk of developing Alzheimer’s disease (AD), and a possible reason for this may be the effects of estrogen depletion and cholinergic system activity following menopause. The investigational radiotracer [18F]‐fluoroethoxybenzovesamicol (FEOBV) can assess in vivo cholinergic integrity, as the tracer binds to the vesicular cholinergic transporter at the synapse. FEOBV has previously shown cholinergic system decline in AD patients. The present study is an investigation of cholinergic system integrity in a sample of cognitively normal postmenopausal women, aged 50‐70 years that were part of a larger study examining cholinergic compensation following menopause. We predicted that higher FEOBV standardized uptake value ratios (SUVR) would be associated with larger basal forebrain cholinergic volumes, lower levels of amyloid SUVR, and better cognitive performance as measured by the RBANS.MethodsTen postmenopausal women (mean age: 57.3 ± 5.1 years) completed an FEOBV PET scan (6.5 mCi dose), MRI and cognitive assessments. The FEOBV PET images were co‐registered to the participant’s structural MRI data. FEOBV SUVR was normalized in reference to the supraventricular white matter to avoid partial volume effects from ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables.ResultsPreliminary analyses showed a positive relationship between FEOBV SUVR and the gray‐matter volume of the cholinergic basal forebrain of both hemispheres (L: r=0.51, R: r=0.65). Two participants were amyloid positive, and their FEOBV SUVR values were lower compared to the amyloid negative participants. A positive relationship was also seen between FEOBV SUVR and the RBANS total score, with higher SUVR associated with better cognitive performance (r=0.43).ConclusionsIn a small sample of cognitively normal postmenopausal women, greater FEOBV uptake was positively associated with both basal forebrain volume and cognitive performance. The results of this pilot sample show the importance of cholinergic system integrity in cognitive performance following menopause, supporting the idea that cholinergic integrity may be linearly related to performance and amyloid aggregation. Deterioration of cholinergic integrity post‐menopause may increase the risk of future cognitive decline and development of AD.

Prognostic value of regional tau PET measures in Alzheimer’s Disease

AbstractBackgroundRecent findings (Ossenkoppele et al, JAMA Neurology, 2021; Pontecorvo et al, Brain, 2019) suggest that tau‐positron emission tomography (PET) may better predict cognitive change in AD compared to amyloid‐PET and MRI‐based cortical thickness. However, the relationship between region‐based standardized uptake value ratio (SUVR) metrics and cognitive change in terms of prognostic value is not clearly understood. In this study, we evaluated the potential utility of region‐based tau‐PET metrics to stratify patients by cognitive decline risk and amyloid status in the brain.MethodsWe analyzed a subgroup of N=100 symptomatic (24 MCI and 76 AD) subjects from the ADNI database that had longitudinal cognitive scores and flortaucipir and florbetapir scans acquired within ±6 months of baseline cognitive scores. We quantified tau burden using global MUBADA SUVR (Devous et al, JNM, 2018) and AAL atlas‐based temporal and parietal regions using a modified cerebellar gray matter reference region (Pontecorvo et al, Brain, 2017). For every global and region‐based tau SUVR, patients were dichotomized into tau groups of high (T+) and low (T‐) by using a series of thresholds (1.15‐1.45). For all identified tau groups, average Mini‐Mental State Exam (MMSE) score, average MUBADA SUVR, percentage of amyloid‐positive individuals and change in 13‐item Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog13) scores were assessed. Signal‐to‐noise ratios (SNRs) and mean annual cognitive changes were measured using ADAS‐Cog13 scores that were obtained in a 2‐to‐3‐year period per patient.ResultsFor every global and region‐based flortaucipir measure, an increase in SUVR threshold resulted in lower average MMSE score, larger average global tau burden, higher percentage of amyloid‐positive patients and increased mean cognitive decline for patients in T+ group. SUVR thresholds that identified subgroups with high percentage (≥90%) of amyloid‐positive (Table 1) and high (&gt;1) SNRs (Table 2), were observed to be lower for brain regions identified later in the tau pathologic cascade: inferior temporal (1.45), lateral temporal (1.35), lateral parietal (1.20).ConclusionsRegion‐based tau‐PET analysis showed that utilizing temporal and parietal SUVR values could help stratify patients by risk of cognitive decline and amyloid status. Clinical trial eligibility algorithms based on region‐based tau metrics, might enable enrolling patients into customized AD trials.

Regional tau PET patterns predict prospective domain‐specific cognitive decline in Alzheimer’s Disease

AbstractBackgroundTau‐PET binding patterns are heterogenous, with regional binding showing strong cross‐sectional correlations with domain‐specific cognitive performance and longitudinal correlations with prospective neurodegeneration. The goal of this study was to evaluate whether regional patterns of baseline tau‐PET predict prospective longitudinal decline in specific cognitive domains in early symptomatic AD.MethodsSeventy‐nine amyloid‐positive participants with a clinical diagnosis of mild cognitive impairment (MCI, n=47) or AD dementia (n=32) underwent a 18Flortaucipir PET (80‐100 minutes after injection), structural MRI, and neuropsychological testing as part of the AVID A05 study (Table 1). Cognitive assessment was repeated after 9 and 18 months. Single‐test annualized w‐scores (age‐corrected z‐scores) at each time point were calculated against 52 controls (age=67.5±10.3) and combined in composite scores for episodic memory, semantic memory, executive function, language, and visuospatial domains. Latent growth curve models were applied to longitudinal composite scores to estimate the rate of annual decline (slope) in each participant. Standardized uptake value ratio (SUVR) images were created using inferior cerebellar gray matter as the reference region. Voxelwise regression analyses were used to identify patterns of baseline tau‐PET associated with longitudinal changes in each cognitive domain. Regression analyses were repeated using cortical regional baseline SUVR values, extracted using FreeSurfer, as predictors of subsequent cognitive decline.ResultsPatients significantly declined in all domains (Figure 1). Differential FTP‐PET patterns showed significant negative associations with domain‐specific annual rates of decline (r≤‐0.3, p&lt;0.001; r≤‐0.5, pFWE&lt;0.05 at voxel level, Figure 2). Specifically, higher tau‐PET SUVR in temporo‐parietal regions was predictive of faster decline in episodic memory, tracer retention in the left anterior temporal lobe related to worse semantic memory, while a more extensive and asymmetric tau‐PET pattern in (L&gt;R) fronto‐temporal regions and (R&gt;L) fronto‐parietal regions related to a faster decline in language and visuospatial domains, respectively. Executive decline showed small inter‐individual variability. Region‐based analyses highlighted similar tau‐PET patterns as predictive of domain‐specific decline (pFDR&lt;0.05, Figure 3).ConclusionAt a group level, differential regional patterns of tau are associated with domain‐specific cognitive decline in MCI and early AD dementia. Tau PET may be a useful precision medicine tool for predicting patient‐specific trajectories in early symptomatic AD.

Correlation of Global and Regional Amyloid Burden by 18 F-Florbetaben PET/CT With Cognitive Impairment Profile and Severity.

To assess the correlation between profile and severity deterioration in the neuropsychological assessment and the most affected regions in amyloid PET semiquantification. The influence of vascular risk and other potential confounding factors was also evaluated. A retrospective, observational, and multicenter study including all patients referred for amyloid PET in daily practice was conducted. Patients underwent neuropsychological assessment, and cognitive decline severity and domain(s) affected were recorded. The patients were grouped according to cognitive impairment (CI) profile and severity: (A) no CI, single-domain amnestic CI, multiple-domain amnestic CI, and nonamnestic CI; and (B) mild CI, moderate and severe dementia. An adapted Framingham Stroke Risk Profile was calculated for each individual. Depression and parkinsonism were also recorded. Standardized quantitative analysis software was used to obtain standardized uptake value ratio (SUVR) values from PET/CT images. The corresponding associations were assessed with the most appropriate statistical tests. One hundred twenty-nine patients were included (62 men, 67 women; 64.67 ± 7.47 years old). Significant differences in global and regional amyloid load were exclusively found in women between non-CI and moderate dementia ( P = 0.006, for total-cerebellum SUVR). Posterior and anterior cingulates and prefrontal cortex best represented CI severity ( P = 0.003, 0.006, and 0.006, respectively). No relationship between the CI profile and the regional amyloid load was shown. A significantly high positive correlation was found between age and vascular risk and between these variables and amyloid load in nearly all regions, especially in women with moderate dementia. Semiquantitative analysis of amyloid PET by SUVR values revealed a significant correlation between amyloid burden and CI severity, although only in women.

Automated semi-quantitative amyloid PET analysis technique without MR images for Alzheimer’s disease

ObjectiveAlthough beta-amyloid (Aβ) positron emission tomography (PET) images are interpreted visually as positive or negative, approximately 10% are judged as equivocal in Alzheimer’s disease. Therefore, we aimed to develop an automated semi-quantitative analysis technique using 18F-flutemetamol PET images without anatomical images.MethodsOverall, 136 cases of patients administered 18F-flutemetamol were enrolled. Of 136 cases, five PET images each with the highest and lowest values of standardized uptake value ratio (SUVr) of cerebral cortex-to-pons were used to create positive and negative templates. Using these templates, PET images of the remaining 126 cases were standardized, and SUVr images were produced with the pons as a reference region. The mean of SUVr values in the volume of interest delineated on the cerebral cortex was compared to those in the CortexID Suite (GE Healthcare). Furthermore, centiloid (CL) values were calculated for the 126 cases using data from the Centiloid Project (http://www.gaain.org/centiloid-project) and both templates. 18F-flutemetamol-PET was interpreted visually as positive/negative based on Aβ deposition in the cortex. However, the criterion "equivocal" was added for cases with focal or mild Aβ accumulation that were difficult to categorize. Optimal cutoff values of SUVr and CL maximizing sensitivity and specificity for Aβ detection were determined by receiver operating characteristic (ROC) analysis using the visual evaluation as a standard of truth.ResultsSUVr calculated by our method and CortexID were highly correlated (R2 = 0.9657). The 126 PET images comprised 84 negative and 42 positive cases of Aβ deposition by visual evaluation, of which 11 and 10 were classified as equivocal, respectively. ROC analyses determined the optimal cutoff values, sensitivity, and specificity for SUVr as 0.544, 89.3%, and 92.9%, respectively, and for CL as 12.400, 94.0%, and 92.9%, respectively. Both semi-quantitative analyses showed that 12 and 9 of the 21 equivocal cases were negative and positive, respectively, under the optimal cutoff values.ConclusionsThis semi-quantitative analysis technique using 18F-flutemetamol-PET calculated SUVr and CL automatically without anatomical images. Moreover, it objectively and homogeneously interpreted positive or negative Aβ burden in the brain as a supplemental tool for the visual reading of equivocal cases in routine clinical practice.

Identifying Mild Alzheimer's Disease With First 30-Min 11C-PiB PET Scan.

Introduction11C-labeled Pittsburgh compound B (11C-PiB) PET imaging can provide information for the diagnosis of Alzheimer's disease (AD) by quantifying the binding of PiB to β-amyloid deposition in the brain. Quantification index, such as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR), has been exploited to effectively distinguish between healthy and subjects with AD. However, these measures require a long wait/scan time, as well as the selection of an optimal reference region. In this study, we propose an alternate measure named amyloid quantification index (AQI), which can be obtained with the first 30-min scan without the selection of the reference region.Methods11C-labeled Pittsburgh compound B PET scan data were obtained from the public dataset “OASIS-3”. A total of 60 mild subjects with AD and 60 healthy controls were included, with 50 used for training and 10 used for testing in each group. The proposed measure AQI combines information of clearance rate and mid-phase PIB retention in featured brain regions from the first 30-min scan. For each subject in the training set, AQI, SUVR, and DVR were calculated and used for classification by the logistic regression classifier. The receiver operating characteristic (ROC) analysis was performed to evaluate the performance of these measures. Accuracy, sensitivity, and specificity were reported. The Kruskal–Wallis test and effect size were also performed and evaluated for all measures. Then, the performance of three measures was further validated on the testing set using the same method. The correlations between these measures and clinical MMSE and CDR-SOB scores were analyzed.ResultsThe Kruskal–Wallis test suggested that AQI, SUVR, and DVR can all differentiate between the healthy and subjects with mild AD (p < 0.001). For the training set, ROC analysis showed that AQI achieved the best classification performance with an accuracy rate of 0.93, higher than 0.88 for SUVR and 0.89 for DVR. The effect size of AQI, SUVR, and DVR were 2.35, 2.12, and 2.06, respectively, indicating that AQI was the most effective among these measures. For the testing set, all three measures achieved less superior performance, while AQI still performed the best with the highest accuracy of 0.85. Some false-negative cases with below-threshold SUVR and DVR values were correctly identified using AQI. All three measures showed significant and comparable correlations with clinical scores (p < 0.01).ConclusionAmyloid quantification index combines early-phase kinetic information and a certain degree of β-amyloid deposition, and can provide a better differentiating performance using the data from the first 30-min dynamic scan. Moreover, it was shown that clinically indistinguishable AD cases regarding PiB retention potentially can be correctly identified.

A residual marker of cognitive reserve modifies the cross‐sectional and longitudinal association between memory and glucose hypometabolism in Alzheimer’s disease

AbstractBackgroundThe cognitive reserve (CR) hypothesis was proposed to explain inter‐individual differences in the association between observed cognitive function and estimated neurodegenerative burden, e.g. in Alzheimer’s disease (AD). Latent CR marker approaches were suggested as a promising method to predict reserve.MethodAmyloid‐β (Aβ)‐negative, cognitively normal and Aβ‐positive, cognitive impaired (Clinical Dementia Rating global score &gt;= 0.5) individuals participating in the AD Neuroimaging Initiative (ADNI) were classified as healthy controls (HC, N=138) and AD spectrum (ADS, Baseline N=462, Follow‐Up N=211), respectively. A latent CR marker (CRM) was obtained by multilinear regression analysis in the entire study cohort, defined as the residual global cognitive performance remaining after accounting for neuropathological burden (CSF Aß42 and total Tau levels and APOE ε4 carrier status) and demographic variables. Mean standardized uptake value ratio (SUVR) values for regions of interests (ROIs) of left and right angular gyrus (L/R‐ANG), bilateral posterior cingulate (PCC), left and right inferior temporal gyrus (L/R‐TEMP) were derived from FDG‐PET data. In separate analyses for HC and ADS, the interactive effects of the memory cognitive composite (MEM) and latent CR marker on FDG‐PET SUVR values were tested for the five cortical ROIs at baseline and 24‐months follow‐up data.ResultIn ADS, higher CRM attenuated the relationship between MEM and FDG‐PET SUVR in L‐TEMP, R‐TEMP and L‐ANG at baseline, and in L‐TEMP, R‐TEMP, L‐ANG and R‐ANG in the longitudinal analyses. In HC, however, no interaction was observed.ConclusionPatients with higher CR maintained their memory performance better in the face of AD‐related glucose hypometabolism . Therefore, the present study supports the use of a residual CRM to improve our understand of inter‐individual differences in the resilience against neurodegeneration, both cross‐sectionally and longitudinally.

Spatial covariance structure of tau‐PET changes more than Aβ‐PET across disease stages

AbstractBackgroundAlzheimer disease (AD) has a long preclinical phase with pathophysiological changes such as β‐amyloid (Aβ) accumulation in early stages followed by tau deposition. Graph theory may provide additional insights into the disease processes underlying patterns of Aβ and tau deposition (Pereira et al., 2018; Hoenig,2018). This project uses graph theory to study the spatial covariance structure of Aβ‐PET and tau‐PET changes across disease stages.MethodThis study includes 254 cognitively normal participants (Clinical Dementia Rating™ (CDR™) =0) and 41 impaired participants (CDR&gt;0) from the Washington University Knight Alzheimer Disease Research Center (ADRC, Funding: P50AG005681; P01AG003991; P01AG026276), who underwent MRI, Aβ‐PET 18F‐AV45, and tau‐PET (18F‐AV1451). Regions of interest were defined using the Freesurfer Desikin atlas. Regional Aβ and tau standardized uptake value ratios (SUVRs) were adjusted by gender and age, and used to generate Pearson correlation matrix. Aβ and tau spatial covariance structure can be built as a collection of nodes representing the mean SUVR values from different brain regions, connected by edges representing correlated deposition quantity. BRAPH toolbox (Mijalkov, 2017) were used to calculate Binary Undirected Density (BUD) graph measures. To test for significant differences between these two groups, BRAPH performs non‐parametric permutation tests. Global graph theory measures (global and local efficiency, and modularity) are used to assess the spatial covariance structure of Aβ‐PET and tau‐PET changes.ResultNo significant difference between the CDR=0 and CDR&gt;0 groups was observed for the global measures generated from the Aβ‐PET data (Table 1 and Figure 1A‐C). However, there were significant differences between the two groups for the global measures generated from the tau‐PET data (Table 1 and Figure 1D‐F). The global and local efficiency were lower in the CDR&gt;0 group (p=0.003 and p=0.018, respectively) indicating a higher global and local path length in the covariance structure. Moreover, the modularity was lower (p=0.005) for CDR&gt;0 group, indicating lower fragmentation between regions in this group.ConclusionChanges in spatial correlation associated with conversion to clinical impairment are happening in the tau pattern. These spatial covariance structure changes need further evaluation to assess their utility as a biomarker of disease progression in the preclinical phase of AD.

Clinical outcomes of increased regional amyloid uptake in patients with subthreshold global amyloid levels

AbstractBackgroundAlthough the standardized uptake value ratio (SUVR) method is objective and simple, cut‐off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to regionally increased β‐amyloid (Aβ) uptake and global Aβ status.MethodWe recruited 973 patients with Alzheimer's disease ‐related cognitive impairment (ADCI). All patients underwent neuropsychological tests and 501 18F‐florbetaben (FBB) amyloid positron emission tomography (PET) and 472 18F‐flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (frontal, temporal, parietal, posterior cingulate, and striatum) by regional quantitative SUVR‐based cutoff values for each region using an iterative outlier approach.ResultA total of 64 (6.6%) subjects showed increased regional Aβ uptake with subthreshold global Aβ status [focal (+) and global (‐) Aβ group, F(+)G(‐) group]. The F(+)G(‐) group showed worse performance in memory impairment (P &lt; 0.001) and greater hippocampal atrophy (P = 0.024) but not global cognition and cortical thickness, compared to those in the F(‐)G(‐). Participants with diffuse Aβ involvement in the whole region [diffuse (+) and global (+) Aβ group, D(+)G(+)] showed worse neuropsychological (P = 0.008‐0.042) and neuroimaging features (P &lt;0.015) than those with focal Aβ involvement F(+)G(+).Conclusion] Our findings suggest that individuals show distinctive clinical outcomes according to regionally increased Aβ uptake and global Aβ status. Thus, clinicians should pay more attention to regional increased Aβ uptake in addition to global Aβ status.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

Region- and voxel-based quantification in human brain of [18F]LSN3316612, a radioligand for O-GlcNAcase

BackgroundPrevious studies found that the positron emission tomography (PET) radioligand [18F]LSN3316612 accurately quantified O-GlcNAcase in human brain using a two-tissue compartment model (2TCM). This study sought to assess kinetic model(s) as an alternative to 2TCM for quantifying [18F]LSN3316612 binding, particularly in order to generate good-quality parametric images.MethodsThe current study reanalyzed data from a previous study of 10 healthy volunteers who underwent both test and retest PET scans with [18F]LSN3316612. Kinetic analysis was performed at the region level with 2TCM using 120-min PET data and arterial input function, which was considered as the gold standard. Quantification was then obtained at both the region and voxel levels using Logan plot, Ichise's multilinear analysis-1 (MA1), standard spectral analysis (SA), and impulse response function at 120 min (IRF120). To avoid arterial sampling, a noninvasive relative quantification (standardized uptake value ratio (SUVR)) was also tested using the corpus callosum as a pseudo-reference region. Venous samples were also assessed to see whether they could substitute for arterial ones.ResultsLogan and MA1 generated parametric images of good visual quality and their total distribution volume (VT) values at both the region and voxel levels were strongly correlated with 2TCM-derived VT (r = 0.96–0.99) and showed little bias (up to − 8%). SA was more weakly correlated to 2TCM-derived VT (r = 0.93–0.98) and was more biased (~ 16%). IRF120 showed a strong correlation with 2TCM-derived VT (r = 0.96) but generated noisier parametric images. All techniques were comparable to 2TCM in terms of test–retest variability and reliability except IRF120, which gave significantly worse results. Noninvasive SUVR values were not correlated with 2TCM-derived VT, and arteriovenous equilibrium was never reached.ConclusionsCompared to SA and IRF, Logan and MA1 are more suitable alternatives to 2TCM for quantifying [18F]LSN3316612 and generating good-quality parametric images.

Altered glucose metabolism of the olfactory-related cortices in anosmia patients with traumatic brain injury.

Impaired brain cortices contribute significantly to the pathophysiological mechanisms of post-traumatic olfactory dysfunction (PTOD). This study aimed to use 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to measure cerebral cortices' metabolism activity and then to explore their associations with olfaction in patients with PTOD. Ethics committee-approved prospective studies included 15 patients with post-traumatic anosmia and 11 healthy volunteers. Olfactory function was assessed using the Sniffin' Sticks. Participants underwent 18F-FDG PET/CT scan and the image data were collected for the voxel-based whole brain analysis. Furthermore, the standardized uptake value ratio (SUVR) of the whole brain regions was measured and correlated with olfactory function. Patients with post-traumatic anosmia showed significantly reduced glucose metabolism in bilateral rectus, bilateral superior and medial orbitofrontal cortex (OFC), bilateral thalamus, left hippocampus and parahippocampus and left superior temporal pole (all p < 0.001). In contrast, patients with post-traumatic anosmia had significantly increased glucose metabolism in the bilateral insula (all p < 0.001). SUVR values among a total of 17 cerebral cortices including frontal, limbic, and temporal regions were significantly and positively correlated with olfactory function. The cerebral cortices with the top three correlations were the right middle frontal OFC (r = 0.765, p = 0.001), right caudate (r = 0.652, p = 0.010) and right putamen (r = 0.623, p = 0.002). Patients with post-traumatic anosmia presented with distinct patterns of brain metabolism and key cortices that highly associated with the retained olfactory function were identified. The preliminary results further support the potential use of PET imaging for precisely assessing brain metabolism in patients with PTOD.

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

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.

Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts.

To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer's Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5pg/mL). FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.

Colocalization of atrophy and tau improves AI classification of Alzheimer phenotypical variants

AbstractBackgroundThe high cognitive and anatomical heterogeneity in phenotypical variants of Alzheimer’s Disease imposes a formidable challenge for biomarker‐based discriminatory models. Motivated by recent findings (La Joie, 2020) suggesting a causal relationship between regional tau accumulation and future atrophy development, we used Machine Learning techniques to test whether colocalization of these two biomarkers could improve clinical differentiation of AD phenotypical variants.MethodWe investigated 85 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 17 patients with PCA, 16 with lvPPA, and 52 typical cases (tAD, Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Thickness measurements were turned into age and sex adjusted z‐scores (Potvin, 2017). Standardized Uptake Value Ratio (SUVR) images were created using reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions (Figure 1). Random Forest (RF) and Support Vector Machines (SVM) were used for supervised classification of patients into one of the three diagnosis above. Four distinct models were compared: based on amyloid, atrophy, tau, or on the product between atrophy and tau (hence capturing the colocalization of these two biomarkers). Selected ROIs were acquired using SVM feature importance and used in a second SVM method (SVM‐ROIs).ResultFigure 2a shows the accuracy of the classification models as a function of the used input features. As a general trend: i) amyloid‐based models had the poorest classification accuracy; ii) tau‐based SVM models outperformed atrophy‐based predictions; iii) the product of atrophy and tau significantly improved accuracy; and iv) in SVM models, selection of a subset of regions consistently improved classifications over those models using all brain regions. Figure 2b shows the confusion matrix for the most accurate model (SVM on selected ROIs).ConclusionIn the cohort used in this study, the product of atrophy and tau provides a better classification feature than each feature considered in isolation. Our results suggest that the colocalization of these two biomarkers represent a valuable instrument for clinical decision‐making in phenotypical variants of AD.