Konstantinos Chiotis

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.

Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study

PET and CSF biomarkers of amyloid-β are considered interchangeable in defining ‘amyloid positivity’. However, Leuzy et al. report discordance between these measures in a multicentre memory clinic population. This suggests that in a minority of individuals these metrics may not be interchangeable, and may instead reflect distinct but interrelated processes.

Concordance and Diagnostic Accuracy of [11C]PIB PET and Cerebrospinal Fluid Biomarkers in a Sample of Patients with Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND Alzheimers disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-β1-42 (Aβ1-42), total-tau (t-tau), and phosphorylated tau (p-tau181p), as well as with positron emission tomography (PET) using [(11)C]Pittsburgh compound-B ([(11)C]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [(11)C]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD. OBJECTIVE To determine concordance and classification accuracy of CSF biomarkers and [(11)C]PIB PET in a cohort of patients with MCI and AD. METHODS 68 patients (MCI, n = 33; AD, n = 35) underwent [(11)C]PIB PET and CSF sampling. Cutoffs of >1.41 ([(11)C]PIB), <450 pg/mL-and a more lenient cutoff of 550 pg/mL-(Aβ1-42), <6.5 (Aβ1-42/p-tau181p), and 1.14 (Aβ1-42/t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI). RESULTS Concordance between [(11)C]PIB and Aβ1-42 was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using Aβ1-42 <550 pg/mL, or Aβ1-42 to tau ratios. Logistic regression showed that classification accuracy of [(11)C]PIB, between sMCI and pMCI, was superior to Aβ1-42 (73% versus 58%), Aβ1-42/t-tau (63%), and Aβ1-42/p-tau181p (65%). CONCLUSION In the present study, [(11)C]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of Aβ1-42 or Aβ1-42/tau. Discordance between PET and CSF markers for Aβ1-42 suggests they cannot be used interchangeably, as is currently the case.

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.

Role of Anthropometric Characteristics in Idiopathic Carpal Tunnel Syndrome

OBJECTIVE To investigate the possible association of external and ultrasonographic measurements of the hand and wrist with median nerve conduction studies. DESIGN Two group comparison study. SETTING Outpatient neurophysiology laboratory and radiology department in a university hospital. PARTICIPANTS Patient group (n=50; 40 women) with clinically overt and electrophysiologically proven idiopathic carpal tunnel syndrome and a control group of age- and sex-matched healthy volunteers (n=50). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES The following measurements were taken: (1) motor and sensory conduction studies of the median nerve; (2) external hand and wrist dimensions (hand ratio and wrist ratio); and (3) ultrasonographic dimensions of the carpal tunnel (carpal tunnel inlet ratio and carpal tunnel outlet ratio) and inlet cross-sectional area and outlet cross-sectional area of the median nerve at the tunnel. RESULTS Differences between patients and controls were significant for hand and wrist ratios and all ultrasonographic dimensions. Sensory conduction velocity and distal motor latency of the median nerve in all 100 subjects were well correlated with hand ratio, wrist ratio, carpal tunnel inlet ratio, and carpal tunnel outlet ratio estimates. Wrist ratio was significantly correlated with carpal tunnel inlet ratio and carpal tunnel outlet ratio. CONCLUSIONS A particular hand and wrist configuration, that is, short and wide hand with square wrist matching to narrow and deep tunnel entrance demonstrated increased liability for idiopathic carpal tunnel syndrome. For screening purposes, it was suggested that simple external hand or wrist measurements could be used to predict the tendency for carpal tunnel syndrome.

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.