Standardized Uptake Value Ratio Images Research Articles

Abstract LB419: Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging

Abstract Introduction: While 5-10 years of aromatase inhibitor (AI) treatment clearly improves survival rates of postmenopausal women with hormone-sensitive breast cancer, up to 85% of AI users report aromatase inhibitor associated musculoskeletal syndrome (AIMSS, including arthralgias, myalgias, and muscle stiffness). The biological mechanisms underlying AIMSS are not well understood, but accumulating preclinical and clinical evidence implicate an important role for neuroinflammation in the development and maintenance of other types of chronic musculoskeletal pain (e.g., low back pain, fibromyalgia etc.). The purpose of this pilot study was to investigate the role of neuroinflammation in breast cancer patients with AIMSS. Methods: This cross-sectional case control study used Siemens 3 T integrated positron emission tomography-magnetic resonance imaging (PET/MRI) with the radioligand [11C]PBR28, which binds to the neuroinflammation marker 18kDa translocator protein (TSPO), to assess neuroinflammation in two cohorts (chronic AIMSS, no-AIMSS) of breast cancer patients undergoing AI therapy, and age-, sex- and TSPO genotype-matched healthy controls. Static [11C]PBR28 PET images were reconstructed from 60-90 minutes post-injection. Standardized uptake value (SUV) maps were obtained voxel-wise by normalizing radioactivity by injected dose/body weight. SUV maps were normalized to whole brain to obtain SUV ratio (SUVR) maps. SUVR images spatially normalized to MNI template and then spatially smoothed (FWHM=8mm). Results: Two breast cancer patients (1 AIMSS, 1 no-AIMSS) and 2 matched healthy controls were included in this analysis. Compared to their individual matched healthy controls, both breast cancer patients showed increased [11C]PBR28 signal uptake in the thalamus/midbrain and pons. This elevated signal was more prominent in the breast cancer patient with AIMSS. Conclusions: These preliminary findings suggest an elevated signal of neuroinflammation in the thalamus and brainstem in AI-treatment and AIMSS, aligning with existing literature emphasizing their pivotal role in chronic pain pathology. While it is imperative to acknowledge the limitation of a small sample size, these promising findings suggest a potential role of neuroinflammation for the first time in AIMSS. Future focused Region of Interest (ROI) analysis in thalamus and brainstem with a larger sample size may confirm. Citation Format: Yehui Zhu, Natalie Swanson, Jennifer Murphy, Minhae Kim, Ann Partridge, Robert Edwards, Kristin Schreiber, Marco Loggia. Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB419.

CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals

AbstractBackgroundCerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.MethodThe first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultTable 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.ConclusionIn CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.

CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals

AbstractBackgroundCerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.MethodThe first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultTable 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.ConclusionIn CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.

The cortical glucose metabolism signatures of cognitive resilience in amyloid positive cognitively unimpaired elderly adults

AbstractBackgroundβ‐amyloid (Aβ) positive (A+) cognitively unimpaired (CU) individuals who maintain normal cognitive function at follow‐up may have good cognitive resilience (CR). A+/CU Individuals with high CR may have hypermetabolism. In this study, we explored the cortical glucose metabolism features of CR in A+/CU elderly adults.MethodWe analyzed 855 ADNI participants with Aβ PET (18F‐florbetapir (FBP) or 18F‐florbetaben (FBB)), CSF p‐Tau181, 18F‐fluorodeoxyglucose (FDG) PET and longitudinal residual hippocampal volume (rHCV) and cognitive assessments. A+/T+/N+ were defined as AD summary cortical standardized uptake value ratio (SUVR) for FBP ≥1.11 or FBB ≥1.08, CSF p‐Tau≥23pg/ml, and rHCV≤‐0.67 respectively. We compared intensity‐ and spatial‐normalized FDG SUVR images between 96 A‐/T‐/N‐/CU individuals (Reference group) and 68 A+/CU individuals who maintained CU at follow‐up regardless of T+ or N+ (CR group). Cortical regions with higher FDG SUVR in the CR group were identified as the CR_metaROI. Baseline CR_metaROI FDG‐SUVRs were compared between different stages of AD. Finally, we determined whether CR_metaROI FDG‐SUVR can modulate the association of Aβ PET and CSF p‐Tau with longitudinal changes of cognition, controlling for age, sex, and education.ResultCR_metaROI was primarily located in the precentral and postcentral regions (Fig. 1). AD dementia patients had lower CR_metaROI FDG SUVRs than the CU (standardized β (βstd) = ‐0.326[95% confidence interval (ci): ‐0.534, ‐0.119], p = 0.002) and MCI (βstd = ‐0.303[95%ci: ‐0.496, ‐0.111], p = 0.002) groups (Fig. 2A), and A+/CU group had higher (βstd = 0.605[95%ci: 0.352, 0.859], p<0.001) CR_metaROI FDG SUVRs than the A‐/CU group (Fig. 2B). A‐/T+ and A+/T‐ individuals had lower (βstd = ‐0.248[95%ci: ‐0.4474, ‐0.022], p = 0.031) and higher (βstd = 0.305[95%ci: 0.093, 0.516], p = 0.005) CR_metaROI FDG SUVRs than the A‐/T‐ group respectively (Fig. 2C). The A+/T‐/N+ group had higher (βstd = 0.466[95%ci: 0.153, 0.779], p = 0.004) CR_metaROI FDG SUVRs than the A‐/T‐/N‐group (Fig. 2D). Moreover, higher baseline metaROI FDG‐SUVRs were associated with slower rates of decline in memory, executive function and preclinical Alzheimer cognitive composite scores upon the same levels of Aβ PET (Fig. 3A‐C) and CSF p‐Tau (Fig. 3D‐F).ConclusionWe identified a metabolism signature of CR in A+/CU elderly adults. These findings may provide novel insights into understanding the hypermetabolism patterns of CR in aging people.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607)

Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90–110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

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.

Voxel‐based correlation of 18F‐THK5351 accumulation with gray matter structural networks in cognitively normal older adults

AbstractBackgroundAlthough gray matter (GM) structural networks based on intracortical similarities have been proposed, no studies have yet examined the correlations between GM network measures and tau. Here, we investigated the voxel‐wise correlations of GM network measures and 18F‐THK5351 accumulation in cognitively normal (CN) older adults.MethodWe recruited 47 amyloid‐negative CN older adults (65.0 ± 7.9 y age, 26 female, 14.3 ± 2.4 y education, Mini‐Mental State Examination score 29.3 ± 1.1, Wechsler Memory Scale‐Revised Logical Memory II score 13.4 ± 2.9). All participants underwent 3D T1‐weighted MRI, 11C‐PiB and 18F‐THK5351 PET scans. Single‐subject GM networks extracted from T1‐weighted MRI data based on intracortical similarities were analyzed using the graph theoretical approach. Correlations between four local network measures (betweenness centrality, clustering coefficient, characteristic path length, and degree) and 18F‐THK5351 standardized uptake value ratio (SUVR) images were evaluated at a voxel level using biological parametric mapping (BPM) toolbox in SPM. The results with the following criteria were deemed significant: a height threshold of p < .05 (family‐wise error corrected) with an extent threshold of 100 voxels.ResultSignificant positive correlations between four local network measures and 18F‐THK5351 SUVR images were detected in the bilateral caudate.ConclusionUsing voxel‐based analysis, we detected significant positive correlations between local network measures and 18F‐THK5351 accumulation in the bilateral caudate in CN older adults. Our findings suggest that tau and neuroinflammation in CN elderly may influence local GM network in the caudate.

18F]RO948 tau PET in bvFTD due to C9orf72 and GRN mutations

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) is characterized by marked changes in personality and behaviour. Approximately 30% of cases are genetic in nature and most commonly due to autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN) genes resulting in TAR DNA‐binding protein 43 (TDP‐43) pathology. Several tau positron emission tomography (PET) studies using [18F]flortaucipir have shown conflicting results regarding tracer retention in bvFTD due to C9orf72 (bvFTD‐C9orf72) and GRN (bvFTD‐GRN) mutations. To date, no studies in bvFTD due to either mutation have been conducted using the novel tau tracer [18F]RO948.MethodEight patients meeting criteria for definite bvFTD were included from the Swedish BioFINDER‐2 study, including seven C9orf72 expansion carriers and one with a GRN mutation. Standardized uptake value ratio (SUVR) images of [18F]RO948 PET were created using 70‐90 post‐injection data and the inferior cerebellar cortex as reference region. Age and sex matched CU individuals (n=9) and patients with Alzheimer’s disease (AD) dementia (n=9) were included for comparison. [18F]RO948 retention in bvFTD mutation carriers was also assessed relative to a larger Aβ‐negative CU group (n=50) using age‐adjusted voxelwise t‐tests.ResultBvFTD‐C9orf72 patients were on average 63 years of age (range 53‐72) and 57% were female. The bvFTD‐GRN patient was a 69‐year‐old male. Comparison of SUVR images showed that [18F]RO948 retention levels in bvFTD mutation carriers were similar to those seen in Aβ‐negative CU individuals (Figure 1). Voxelwise t‐tests showed no significant differences in comparison to the Aβ‐negative CU group. Similar findings were seen using a composite frontal region of interest (ROI) and when using the brainstem as reference instead of the inferior cerebellar cortex.ConclusionThese preliminary findings suggest that [18F]RO948 signal is specific for AD‐type tau and does not capture TDP‐43 type pathology.

Impact of APOE‐ε4 on cerebral amyloid deposition in participants with abnormal soluble amyloid levels

AbstractBackgroundAmyloid pathology can be detected using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging, even though they measure two distinct beta‐amyloid (Aβ) pools. While CSF Aβ concentrations reflect the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques in the brain tissue. Many studies have shown the concordance between the two measures in individuals along the Alzheimer’s continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for Alzheimer’s disease (AD), affects the pattern of cerebral Aβ load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR = 0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ40 and Aβ42 concentrations were determined with the Roche NeuroToolKit (Roche Diagnostics) and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxel‐wise regression was performed to predict FTM uptake, with the following independent variables: age, sex, APOE‐ε4, and CSF Aβ42/40 ratio. Statistical threshold was set to p < 0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ42/40 ratio was negatively associated with cerebral FTM uptake (Figure 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM‐binding across the whole sample (Figure 2b‐2c). Importantly, we found a significant interaction between CSF Aβ42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Figure 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers showed higher cerebral Ab load for any given level of CSF Aβ42/40 in areas that are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the Alzheimer’s continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.

Impact of the APOE gene on amyloid deposition in participants with abnormal soluble amyloid levels

AbstractBackgroundAmyloid pathology can be quantified both in the cerebro‐spinal fluid (CSF) and in positron emission tomography (PET) images, even though they measure two distinct amyloid pools. While CSF Aβ reflects the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques. Many studies have shown the concordance of the two measures in individuals along the Alzheimer’s disease (AD) continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for AD, affects the pattern of cerebral Aβ‐load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR=0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]Flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ‐40 and Aβ‐42 concentrations were determined with the NeuroToolKit (Roche Diagnostics International Ltd.) on a Elecsys cobas e‐411 instrument and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxelwise regression to predict FTM uptake was performed, with the following independent variables: Age, Sex, APOE‐ε4, and CSF Aβ‐42/40. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ‐42/40 was strongly and negatively associated to cerebral FTM uptake (Fig. 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM binding across the whole sample (Fig. 2b‐2c). Importantly, we found a significant interaction between Aβ‐42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Fig. 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers show higher cerebral amyloid load for any given level of CSF Aβ 42/40 in areas which are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the AD continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.

Noninvasive Measurement of [11C]PiB Distribution Volume Using Integrated PET/MRI.

A noninvasive image-derived input function (IDIF) method using PET/MRI was applied to quantitative measurements of [11C] Pittsburgh compound-B (PiB) distribution volume (DV) and compared with other metrics. Fifty-three patients suspected of early dementia (71 ± 11 y) underwent 70 min [11C]PiB PET/MRI. Nineteen of them (68 ± 11 y) without head motion during the scan were enrolled in this study and compared with 16 age-matched healthy controls (CTL: 68 ± 11 y). The dynamic frames reconstructed from listmode PET data were used for DV calculation. IDIF with metabolite correction was applied to the Logan plot method, and DV was normalized into DV ratio (DVR) images using the cerebellar reference (DVRL). DVR and standardized uptake value ratio (SUVR) images were also calculated using the reference tissue graphical method (DVRr) and the 50–70 min static data with cerebellar reference, respectively. Cortical values were compared using the 3D-T1WI MRI segmentation. All patients were assigned to the early Alzheimer’s disease (eAD) group because of positive [11C]PiB accumulation. The correlations of regional values were better for DVRL vs. DVRr (r2 = 0.97) than for SUVR vs. DVRr (r2 = 0.88). However, all metrics clearly differentiated eAD from CTL with appropriate thresholds. Noninvasive quantitative [11C]PiB PET/MRI measurement provided equivalent DVRs with the two methods. SUVR images showed acceptable results despite inferior variability and image quality to DVR images.

Classification of negative and positive 18F-florbetapir brain PET studies in subjective cognitive decline patients using a convolutional neural network

PurposeVisual reading of 18F-florbetapir positron emission tomography (PET) scans is used in the diagnostic process of patients with cognitive disorders for assessment of amyloid-ß (Aß) depositions. However, this can be time-consuming, and difficult in case of borderline amyloid pathology. Computer-aided pattern recognition can be helpful in this process but needs to be validated. The aim of this work was to develop, train, validate and test a convolutional neural network (CNN) for discriminating between Aß negative and positive 18F-florbetapir PET scans in patients with subjective cognitive decline (SCD).Methods18F-florbetapir PET images were acquired and visually assessed. The SCD cohort consisted of 133 patients from the SCIENCe cohort and 22 patients from the ADNI database. From the SCIENCe cohort, standardized uptake value ratio (SUVR) images were computed. From the ADNI database, SUVR images were extracted. 2D CNNs (axial, coronal and sagittal) were built to capture features of the scans. The SCIENCe scans were randomly divided into training and validation set (5-fold cross-validation), and the ADNI scans were used as test set. Performance was evaluated based on average accuracy, sensitivity and specificity from the cross-validation. Next, the best performing CNN was evaluated on the test set.ResultsThe sagittal 2D-CNN classified the SCIENCe scans with the highest average accuracy of 99% ± 2 (SD), sensitivity of 97% ± 7 and specificity of 100%. The ADNI scans were classified with a 95% accuracy, 100% sensitivity and 92.3% specificity.ConclusionThe 2D-CNN algorithm can classify Aß negative and positive 18F-florbetapir PET scans with high performance in SCD patients.

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

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.

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients.

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results: 18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification.

The Precuneus – A Witness for Excessive Aβ Gathering in Alzheimer’s Disease Pathology

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer’s disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Αβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [¹⁸F]-flor­betapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses.

The effect of ApoE ε4 on longitudinal brain region-specific glucose metabolism in patients with mild cognitive impairment: a FDG-PET study.

While the ApoE ε4 allele is a known risk factor for mild cognitive impairment (MCI) and Alzheimer's disease, brain region specific effects remain elusive. In this study, we investigate whether the ApoE ε4 allele exhibits brain region specific effects in longitudinal glucose uptake among patients with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed FDG PET images, MRIs, and demographic information were downloaded from the ADNI database. An iterative reblurred Van Cittertiteration method was used for partial volume correction (PVC) on all PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. Longitudinal changes in ROI FDG standardized uptake value ratio (SUVR) relative to cerebellum in 24 ApoE ε4 carriers and 24 age-matched ApoE ε4 non-carriers were measured for up to 84-months (median 72 months, SD = 11.2 months) and compared using a generalized linear mixed effects model controlling for gender, education, baseline age, and follow-up period. Additionally, voxelwise analysis was performed by implementing a paired t-test comparing matched baseline and 72 month FDG SUVR images in ApoE carriers and non-carriers separately. Results with PVC were compared with ones from non-PVC based analysis. After applying PVC, the superior fontal, parietal, lateral temporal, medial temporal, caudate, thalamus, and post-cingulate, and amygdala regions had greater longitudinal decreases in FDG uptake in ApoE ε4 carriers with MCI compared to non-carriers with MCI. Similar forebrain and limbic clusters were found through voxelwise analysis. Compared to the PVC based analysis, fewer significant ApoE-associated regions and clusters were found in the non-PVC based PET analysis. Our findings suggest that the ApoE ε4 genotype is associated with a longitudinal decline in glucose uptake in 8 forebrain and limbic brain regions in the context of MCI. In conclusion, this 84-months longitudinal FDG PET study demonstrates a novel ApoE ε4-associated brain-region specific glucose metabolism pattern in patients with MCI. Partial volume correction improved FDG PET quantification.

COMBINATORIAL SENSORY MODALITY ASSESSMENT IN PRODROMAL ALZHEIMER’S DISEASE: RELATION TO MRI AND AMYLOID AND TAU PET

Measures of sensory function, including vision and smell, have been shown to be impaired in Alzheimer's disease (AD), even in prodromal stages. Our goal was to evaluate whether visual function and smell identification combined would provide a better prediction of AD pathology (i.e., cortical amyloid deposition, medial temporal lobe (MTL) tau deposition, MTL atrophy) than either measure alone in a cohort of cognitively normal older adults (CN), older adults with subjective cognitive decline (SCD), and mild cognitive impairment patients (MCI). 34 individuals (14 CN, 11 SCD, 9 MCI) underwent assessments of visual contrast sensitivity (via frequency doubling technology), olfactory identification (the UPSIT), amyloid PET with either [18F]Florbetapir (FBP) or [18F]Florbetaben (FBB), tau PET with [18F]Flortaucipir (FTP), and MRI. Scans were collected using ADNI-2/3 protocols for amyloid PET, tau PET, and MPRAGE (http://www.adni-info.org). Scans were processed using standard techniques to generate smoothed, normalized static images from 50-70min (FBP), 90-110min (FBB), or 80-100min (FTP). Standardized uptake value ratio images (SUVR) were generated using the appropriate reference region (whole cerebellum for FBP, cerebellar grey matter for FBB, cerebellar crus for FTP). SUVR values from the cerebral cortex (for amyloid measures) and the MTL (includes entorhinal cortex, fusiform, and parahippocampal gyri; for FTP) were extracted. Entorhinal cortex (EC) thickness was determined using Freesurfer v5.1. Linear regression models were completed to determine whether contrast sensitivity and UPSIT total score together predict amyloid (z-scored relative to ADNI CN), tau, and atrophy better than either measure alone, covaried for age as needed. In combination, the visual and olfactory measures predicted amyloid, tau, and EC thickness, with poorer performance associated with more amyloid and tau and thinner EC (p<0.05; Table 1, Figure 1A, 2A, 3A). Lower visual contrast sensitivity alone predicted higher tau (p<0.001; Figure 2B), while lower UPSIT score alone predicted a thinner EC (p=0.021, Figure 3C). Relationship of Sensory Measures with Amyloid Deposition Relationship of Sensory Measures with Tau Deposition Relationship of Sensory Measures and Entorhinal Cortex Thickness In general, the combination of both a visual and an olfactory measure showed a better prediction of amyloid, tau, and neurodegeneration. These findings suggest that multi-modal vs single modality sensory assessment may provide a better estimation of AD-related pathology during preclinical and prodromal disease stages.

Distinct [18F]THK5351 binding patterns in primary progressive aphasia variants

PurposeTo assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology.MethodsThe study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction.ResultsPatients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results.Conclusion[18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment.

Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages.

SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

Cerebral metabolism and perfusion in MR-negative individuals with refractory focal epilepsy assessed by simultaneous acquisition of (18)F-FDG PET and arterial spin labeling.

The major challenge in pre-surgical epileptic patient evaluation is the correct identification of the seizure onset area, especially in MR-negative patients. In this study, we aimed to: (1) assess the concordance between perfusion, from ASL, and metabolism, from 18F-FDG, acquired simultaneously on PET/MR; (2) verify the utility of a statistical approach as supportive diagnostic tool for clinical readers. Secondarily, we compared 18F-FDG PET data from the hybrid PET/MR system with those acquired with PET/CT, with the purpose of validate the reliability of 18F-FDG PET/MR data.Twenty patients with refractory focal epilepsy, negative MR and a defined electro-clinical diagnosis underwent PET/MR, immediately followed by PET/CT. Standardized uptake value ratio (SUVr) and cerebral blood flow (CBF) maps were calculated for PET/CT-PET/MR and ASL, respectively. For all techniques, z-score of the asymmetry index (zAI) was applied for depicting significant Right/Left differences. SUVr and CBF images were firstly visually assessed by two neuroimaging readers, who then re-assessed them considering zAI for reaching a final diagnosis.High agreement between 18F-FDG PET/MR and ASL was found, showing hypometabolism and hypoperfusion in the same hemisphere in 18/20 patients, while the remaining were normal. They were completely concordant in 14/18, concordant in at least one lobe in the remaining. zAI maps improved readers' confidence in 12/20 and 15/20 patients for 18F-FDG PET/MR and ASL, respectively. 18F-FDG PET/CT-PET/MR showed high agreement, especially when zAI was considered.The simultaneous metabolism-perfusion acquisition provides excellent concordance on focus lateralisation and good concordance on localisation, determining useful complementary information.