Laure Saint-Aubert

Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

See Schott and Fox (doi: 10.1093/brain/awv405 ) for a scientific commentary on this article. The relationships between pathophysiological processes in Alzheimer’s disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer’s disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

The diagnosis of Alzheimers disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimers disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimers disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.

Tau PET imaging: present and future directions.

Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3. These tracers are now available for clinical assessment in patients with various tauopathies, including Alzheimer’s disease, as well as in healthy subjects. Exploring the patterns of tau deposition in vivo for different pathologies will allow discrimination between neurodegenerative diseases, including different tauopathies, and monitoring of disease progression. The variety and complexity of the different types of tau deposits in the different diseases, however, has resulted in quite a challenge for the development of tau PET tracers. Extensive work remains in order to fully characterize the binding properties of the tau PET tracers, and to assess their usefulness as an early biomarker of the underlying pathology. In this review, we summarize recent findings on the most promising tau PET tracers to date, discuss what has been learnt from these findings, and offer some suggestions for the next steps that need to be achieved in a near future.

White matter disruption at the prodromal stage of Alzheimer's disease: Relationships with hippocampal atrophy and episodic memory performance

White matter tract alterations have been consistently described in Alzheimers disease (AD). In particular, limbic fronto-temporal connections, which are critical to episodic memory function, may degenerate early in the course of the disease. However the relation between white matter tract degeneration, hippocampal atrophy and episodic memory impairment at the earliest stages of AD is still unclear. In this magnetic resonance imaging study, white matter integrity and hippocampal volumes were evaluated in patients with amnestic mild cognitive impairment due to AD (Albert et al., 2011) (n = 22) and healthy controls (n = 15). Performance in various episodic memory tasks was also evaluated in each participant. Relative to controls, patients showed a significant reduction of white matter fractional anisotropy (FA) and increase of radial diffusivity (RD) in the bilateral uncinate fasciculus, parahippocampal cingulum and fornix. Within the patient group, significant intra-hemispheric correlations were notably found between hippocampal grey matter volume and FA in the uncinate fasciculus, suggesting a relationship between atrophy and disconnection of the hippocampus. Moreover, episodic recognition scores were related with uncinate fasciculus FA across patients. These results indicate that fronto-hippocampal connectivity is reduced from the earliest pre-demential stages of AD. Disruption of fronto-hippocampal connections may occur progressively, in parallel with hippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory.

Tracer Kinetic Analysis of (S)-18F-THK5117 as a PET Tracer for Assessing Tau Pathology

Because a correlation between tau pathology and the clinical symptoms of Alzheimer disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-18F-THK5117. Methods: Nine subjects (5 with AD, 4 with mild cognitive impairment) received a 90-min dynamic (S)-18F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. Volume-of-interest (VOI)–based analysis was performed using plasma-input models; single-tissue and 2-tissue (2TCM) compartment models and plasma-input Logan and reference tissue models; and simplified reference tissue model (SRTM), reference Logan, and SUV ratio (SUVr). Cerebellum gray matter was used as the reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan, and SUVr. Regionally averaged voxel values were compared with VOI-based values from the optimal reference tissue model, and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40- and 60-min data were analyzed. Results: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2 = 0.99, slope = 0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2 = 1.00, slope ≈ 1.00) whereas SUVr70–90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2 = 0.99, slope = 1.03). SUVr70–90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in gray matter. Simulations showed poorer accuracy and precision for SUVr70–90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min. Conclusion: SRTM BPND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-18F-THK5117 DVR-1 parametric images with the greatest accuracy and precision and with a much lower white-matter signal than seen with SUVr70–90-1 images.

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

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

Regional tau deposition measured by [18F]THK5317 positron emission tomography is associated to cognition via glucose metabolism in Alzheimer’s disease

BackgroundThe recent development of tau-specific positron emission tomography (PET) tracers has allowed in vivo quantification of regional tau deposition and offers the opportunity to monitor the progression of tau pathology along with cognitive impairment. In this study, we investigated the relationships of cerebral tau deposition ([18F]THK5317-PET) and metabolism ([18F]FDG-PET) with concomitant cognitive function in patients with probable Alzheimer’s disease (AD).MethodsNine patients diagnosed with AD dementia and 11 with prodromal AD (mild cognitive impairment, amyloid-positive on [11C]PiB-PET) were included in this study. All patients underwent PET scans using each tracer, as well as episodic memory and global cognition assessment. Linear models were used to investigate the association of regional [18F]THK5317 retention and [18F]FDG uptake with cognition. The possible mediating effect of local metabolism on the relationship between tau deposition and cognitive performance was investigated using mediation analyses.ResultsSignificant negative associations were found between [18F]THK5317 regional retention, mainly in temporal regions, and both episodic memory and global cognition. Significant positive associations were found between [18F]FDG regional uptake and cognition. The association of [18F]FDG with global cognition was regionally more extensive than that of [18F]THK5317, while the opposite was observed with episodic memory, suggesting that [18F]THK5317 retention might be more sensitive than [18F]FDG regional uptake to early cognitive impairment. Finally, [18F]FDG uptake had a mediating effect on the relationship between [18F]THK5317 retention in temporal regions and global cognition.ConclusionsThese findings suggest a mediating role for local glucose metabolism in the observed association between in vivo tau deposition and concomitant cognitive impairment in AD.

Comparison of Early-Phase 11C-Deuterium-l-Deprenyl and 11C-Pittsburgh Compound B PET for Assessing Brain Perfusion in Alzheimer Disease

The PET tracer 11C-deuterium-L-deprenyl (11C-DED) has been used to visualize activated astrocytes in vivo in patients with Alzheimer disease (AD). In this multitracer PET study, early-phase 11C-DED and 11C-Pittsburgh compound B (11C-PiB) (eDED and ePiB, respectively) were compared as surrogate markers of brain perfusion, and the extent to which 11C-DED binding is influenced by brain perfusion was investigated. Methods: 11C-DED, 11C-PiB, and 18F-FDG dynamic PET scans were obtained in age-matched groups comprising AD patients (n = 8), patients with mild cognitive impairment (n = 17), and healthy controls (n = 16). A modified reference Patlak model was used to quantify 11C-DED binding. A simplified reference tissue model was applied to both 11C-DED and 11C-PiB to measure brain perfusion relative to the cerebellar gray matter (R1) and binding potentials. 11C-PiB retention and 18F-FDG uptake were also quantified as target-to-pons SUV ratios in 12 regions of interest (ROIs). Results: The strongest within-subject correlations with the corresponding R1 values (R1,DED and R1,PiB, respectively) and with 18F-FDG uptake were obtained when the eDED and ePiB PET data were measured 1–4 min after injection. The optimum eDED/ePiB intervals also showed strong, significant ROI-based intersubject Pearson correlations with R1,DED/R1,PiB and with 18F-FDG uptake, whereas 11C-DED binding was largely independent of brain perfusion, as measured by eDED. Corresponding voxelwise correlations confirmed the ROI-based results. Temporoparietal eDED or ePiB brain perfusion measurements were highly discriminative between patient and control groups, with discriminative ability statistically comparable to that of temporoparietal 18F-FDG glucose metabolism. Hypometabolism extended over wider regions than hypoperfusion in patient groups compared with controls. Conclusion: The 1- to 4-min early-frame intervals of 11C-DED or 11C-PiB are suitable surrogate measures for brain perfusion. 11C-DED binding is independent of brain perfusion, and thus 11C-DED PET can provide information on both functional (brain perfusion) and pathologic (astrocytosis) aspects from a single PET scan. In comparison with glucose metabolism, early-phase 11C-DED and 11C-PiB perfusion appear to provide complementary rather than redundant information.

Comparability of [18F]THK5317 and [11C]PIB blood flow proxy images with [18F]FDG positron emission tomography in Alzheimer’s disease

For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R1) has been shown to serve as a marker of brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal Alzheimer’s disease and nine Alzheimer’s disease dementia patients underwent [18F]THK5317, carbon-11 Pittsburgh Compound-B ([11C]PIB), and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography to assess the possible use of early-phase [18F]THK5317 and R1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal vs Alzheimers disease dementia) of [18F]THK5317 (early-phase SUVr and R1) was compared with that of [11C]PIB (early-phase SUVr and R1) and [18F]FDG. Strong positive correlations were found between [18F]THK5317 (early-phase, R1) and [18F]FDG, particularly in frontal and temporoparietal regions. Differences in correlations between early-phase and R1 ([18F]THK5317 and [11C]PIB) and [18F]FDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. Our findings suggest that early-phase [18F]THK5317 and R1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single positron emission tomography study with [18F]THK5317 may provide information about both tau pathology and brain perfusion in Alzheimer’s disease, with potential clinical applications.

Comparison of Early-Phase 11C-Deuterium-L-Deprenyl and 11C-PiB PET for Assessing Brain Perfusion in Alzheimer's Disease

The PET tracer 11C-deuterium-L-deprenyl (11C-DED) has been used to visualize activated astrocytes in vivo in patients with Alzheimer disease (AD). In this multitracer PET study, early-phase 11C-DED and 11C-Pittsburgh compound B (11C-PiB) (eDED and ePiB, respectively) were compared as surrogate markers of brain perfusion, and the extent to which 11C-DED binding is influenced by brain perfusion was investigated. Methods: 11C-DED, 11C-PiB, and 18F-FDG dynamic PET scans were obtained in age-matched groups comprising AD patients (n = 8), patients with mild cognitive impairment (n = 17), and healthy controls (n = 16). A modified reference Patlak model was used to quantify 11C-DED binding. A simplified reference tissue model was applied to both 11C-DED and 11C-PiB to measure brain perfusion relative to the cerebellar gray matter (R1) and binding potentials. 11C-PiB retention and 18F-FDG uptake were also quantified as target-to-pons SUV ratios in 12 regions of interest (ROIs). Results: The strongest within-subject correlations with the corresponding R1 values (R1,DED and R1,PiB, respectively) and with 18F-FDG uptake were obtained when the eDED and ePiB PET data were measured 1–4 min after injection. The optimum eDED/ePiB intervals also showed strong, significant ROI-based intersubject Pearson correlations with R1,DED/R1,PiB and with 18F-FDG uptake, whereas 11C-DED binding was largely independent of brain perfusion, as measured by eDED. Corresponding voxelwise correlations confirmed the ROI-based results. Temporoparietal eDED or ePiB brain perfusion measurements were highly discriminative between patient and control groups, with discriminative ability statistically comparable to that of temporoparietal 18F-FDG glucose metabolism. Hypometabolism extended over wider regions than hypoperfusion in patient groups compared with controls. Conclusion: The 1- to 4-min early-frame intervals of 11C-DED or 11C-PiB are suitable surrogate measures for brain perfusion. 11C-DED binding is independent of brain perfusion, and thus 11C-DED PET can provide information on both functional (brain perfusion) and pathologic (astrocytosis) aspects from a single PET scan. In comparison with glucose metabolism, early-phase 11C-DED and 11C-PiB perfusion appear to provide complementary rather than redundant information.