E. Rodriguez-Vieitez

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.

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.

Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography

Studying autosomal dominant Alzheimer’s disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer’s disease (AD) because reactive astrocytes surround β-amyloid (Aβ) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar Aβ, astrocytosis and cerebral glucose metabolism with the radiotracers 11C-Pittsburgh compound-B (PIB), 11C-deuterium-L-deprenyl (DED) and 18F-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar Aβ or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.

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.

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.

Shell structure at N=28 near the dripline: Spectroscopy of Si-42, P-43, and S-44

Measurements of the N=28 isotones 42Si, 43P and 44S using one- and two-proton knockout reactions from the radioactive beam nuclei 44S and 46Ar are reported. The knockout reaction cross sections for populating 42Si and 43P and a 184 keV gamma-ray observed in 43P establish that the d_{3/2} and s_{1/2} proton orbits are nearly degenerate in these nuclei and that there is a substantial Z=14 subshell closure separating these two orbits from the d_{5/2} orbit. The increase in the inclusive two-proton knockout cross section from 42Si to 44S demonstrates the importance of the availability of valence protons for determining the cross section. New calculations of the two-proton knockout reactions that include diffractive effects are presented. In addition, it is proposed that a search for the d_{5/2} proton strength in 43P via a higher statistics one-proton knockout experiment could help determine the size of the Z=14 closure.

Case Report of Complex Amyotrophic Lateral Sclerosis with Cognitive Impairment and Cortical Amyloid Deposition

Amyotrophic lateral sclerosis (ALS), a fatal disease of unknown origin, affects motor neurons in the primary motor cortex, brainstem, and spinal cord. Cognitive impairment may occur before the motor symptoms. We present a patient who was initially diagnosed with mild cognitive impairment (MCI) due to Alzheimers disease (AD) but who developed ALS-like symptoms during follow-up and died shortly thereafter. A 60-year-old subject with cognitive impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) analysis, structural imaging (computed tomography and magnetic resonance imaging) and functional imaging [11C]-Pittsburgh compound B (PIB) positron emission tomography (PET), [18F]-fluorodeoxyglucose (FDG) PET, and [11C]-deuterium-L-deprenyl (DED) PET. Neuropsychological testing showed episodic memory impairment. CSF P-tau and T-tau levels were elevated. CSF amyloid-β (Aβ)42 levels were initially normal but became pathological during follow-up. MCI was diagnosed. [18F]-FDG PET showed hypometabolism in the left temporal and prefrontal cortices and [11C]-PIB PET demonstrated amyloid plaque deposition in the prefrontal, posterior cingulate, and parietal cortices. [11C]-DED PET showed high brain accumulation consistent with astrocytosis. The memory impairment progressed and AD was diagnosed. Motor impairments developed subsequently and, following additional neurological evaluation, ALS was diagnosed. The disease progressed rapidly and the patient died with pronounced motor symptoms three years after the initial cognitive assessment. Since relatives refused autopsy, postmortem analysis was not possible.

Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer’s Disease

OBJECTIVES The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimers disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. METHODS Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. RESULTS In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. CONCLUSIONS The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers. (JINS, 2017, 23, 195-203).