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The odd���odd nucleus �����Na is studied via a one-proton, one-proton���one-neutron and one-neutron removal reaction using an intermediate-energy ����Mg, ����Mg and ����Na radioactive ion beam, respectively. Combining high-resolution ��-ray spectroscopy with the selectivity of the three reaction mechanisms, we are able to distinguish multiple particle���hole configurations. Negative-parity states in �����Na are observed for the first time, providing an important measure of the excitation of the 1p1h/3p3h configuration and hence the sd���pf shell gap. The extracted band structures and level energies serve as invaluable input for the theoretical refinement of the effective interactions used in this region.

Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer’s disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β42and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ2(1) = 5.40;p χ2(1) = 18.86;p APOE-ε4ε4 prevalence (χ2(6) = 197;p n = 867) and slower rate of brain amyloid-β accumulation (F(3,600) = 12.76;p n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways (“CSF-first” vs. “PET-first”) toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.

Altres ajuts: This work was financially supported by grants from the Swedish Research Council (projects 2017-02965, 2017-06086, K2014-61×-05817), the Swedish Foundation for Strategic Research (SSF, project RB13-0192), the Knut and Alice Wallenberg Foundation, the Stockholm County Council-Karolinska Institutet regional agreement on medical training and clinical research (ALF grant), GE Healthcare (unrestricted grant), the Swedish Brain Foundation, the Alzheimer Foundation in Sweden, the Dementia Association, Swedish Brain Power, the EU FP7 large-scale integrating project INMiND (uni-muenster.de/INMiND), the Foundation for Old Servants, Karolinska Institutet's Foundation for Aging Research, Gun and Bertil Stohne's Foundation, Loo and Hans Osterman's Foundation, the Åhlén Foundation, the Åke Wiberg Foundation, and the Departament de Salut de la Generalitat de Catalunya, Pla estratègic de recerca i innovació en salut (PERIS) 2016-2020 (SLT006/17/95). To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with 11 C-deuterium-L-deprenyl (11 C-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD). The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent 11 C-DED-PET. Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11 C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11 C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11 C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness. Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.

Neuroinflammation, as defined by the activation of microglia and astrocytes, has emerged in the last years as a key element of the pathogenesis of neurodegenerative diseases based on genetic findings and preclinical and human studies. This has raised the need for new methodologies to assess and follow glial activation in patients, prompting the development of PET ligands for molecular imaging of glial cells and novel structural MRI and DTI tools leading to a multimodal approach. The present review describes the recent advancements in microglia and astrocyte biology in the context of health, ageing and Alzheimer’s disease, the most common dementia worldwide. The review further delves in molecular imaging discussing the challenges associated with past and present targets, including conflicting findings, and finally presenting novel methodologies currently explored to improve our in vivo knowledge of the neuroinflammatory patterns in Alzheimer’s disease. With glial cell activation as a potential therapeutic target in neurodegenerative diseases, the translational research between cell biologists, chemists, physicists, radiologists and neurologists should be strengthened.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed, and how clinical trials are designed today. Alzheimer's disease (AD)-the most common neurodegenerative disorder-is characterized by a complex neuropathology involving the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells-astrocytes and microglia-and neuroinflammatory responses, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers are available to selectively target the different pathophysiological processes of AD. Along with the success of Aβ PET and the more recent tau PET imaging, there is also a great interest to develop PET tracers to image glial activation and neuroinflammation. While most research to date has focused on imaging microgliosis, recent studies using 11C-deuterium-L-deprenyl (11C-DED) PET imaging suggest that astrocytosis may be present from very early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aβ deposition, and glucose metabolism in patients at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial responses in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial activation and neuroinflammation as biomarkers with clinical application, and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.

Longitudinal FDG and PiB-PET uptake in SUVr(/pons and/cerebellar gray matter) units in brothers A and B compared with the control group of noncarriers in representative ROIs. GM Gray matter, PCC Posterior cingulate cortex, SUVr Standardized uptake value ratio, Temp Temporal. (PDF 125 kb)