PET tau and amyloid-β burden in mild Alzheimer's disease: divergent relationship with age, cognition and cerebrospinal fluid biomarkers

Background Combining PET amyloid-β and tau imaging may be critical for tracking disease progression in Alzheimer’s disease (AD). Objective We sought to characterize the relationship between amyloid-β and tau ligands as well as with other measures of pathology. Methods We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 years. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with amyloid-β ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. Results 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical amyloid-β associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not amyloid-β. Conclusion The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker – the CSF total tau/Aβratio

Imaging Aβ and tau in early stage Alzheimer’s disease with [18F]AV45 and [18F]AV1451

Abstract Background AD is a progressive neurodegenerative disorder that is associated with the accumulation of two different insoluble protein aggregates, Aβ plaques and hyperphosphorylated tau. This study aimed to investigate the optimal acquisition and quantification of [18F]AV45 and [18F]AV1451 to image Aβ and tau, respectively, in subjects with AD. Fifteen subjects with early stage AD underwent a T1-weighted structural MRI and two dynamic PET scans to image Aβ (60 min, [18F]AV45) and tau (120 min, [18F]AV1451). Both dynamic BPND and static SUVR outcome measures were calculated and compared for 12 out of 15 subjects who completed 60 min of the Aβ PET scan and at least 110 min of the tau PET scan. The SRTM and reference Logan graphical analysis were applied to the dynamic data to estimate regional BPND values and SUVR ratios from the static data. Optimal acquisition windows were explored for both the dynamic and static acquisitions. In addition, the spatial correlation between regional Aβ and tau signals was explored. Results Both the SRTM and graphical analysis methods showed a good fit to the dynamic data for both Aβ and tau dynamic PET scans. Mean regional BPND estimates became stable 30 min p.i. for [18F]AV45 and 80 min p.i. for [18F]AV1451. Time stability analysis of static SUVR data showed that the outcome measure starts to become stable for scan windows of 30–50 min p.i. for [18F]AV45 and 80–100 min p.i. for [18F]AV1451. The results from these time windows correlated well with the results from the full dynamic analysis for both tracers (R 2 = 0.74 for [18F]AV45 and R 2 = 0.88 for [18F]AV1451). There was a high correlation between amyloid uptake estimate using both dynamic analysis methods in thalamus and tau uptake in thalamus, hippocampus and amygdala. Conclusions Short static PET scans at appropriate time windows provided SUVR values which were in reasonable agreement with BPND values calculated from dynamic scans using SRTM and reference Logan. These simplified methods may be appropriate for classification and intervention studies, although caution should be employed when considering interventional studies where blood flow and extraction could change

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological "signatures" of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological “signatures” of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics.

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological "signatures" of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies

Gait in mild Alzheimer’s disease: feasibility of multi-centre measurement in the clinic and home with body-worn sensors: a pilot study

Gait is emerging as a potential diagnostic tool for cognitive decline. The ‘Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study’ (D&FP;) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer’s disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD

Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study.

Gait is emerging as a potential diagnostic tool for cognitive decline. The 'Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study' (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer's disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD