#15
Agneta Nordberg

PET imaging markers in neurodegenerative diseases – the present and future

Abstract: There has been a rapid development during recent years in the field of molecular brain imaging in neurodegenerative disease especially for Alzheimer’s disease (AD). New PET tracers have led to important further insights and understanding of  pathological processes detectable  even long before clinical symptoms. This has led to not only development of new diagnostic markers but also implications for drug treatment and clinical praxis. A new era of proteomics of PET was initiated with Pittsburgh compound B  (11C-PIB) as the first PET tracer targeting amyloid protein in brain of AD patients. 11C-PIB was soon followed by the amyloid PET tracers 18F-flutemetamol,18F-Florbetapir, 18F-florbetaben, all approved by FDA and EMA as radioactive diagnostic agents. Amyloid PET has provided important understanding of the time course of amyloid plaque deposition in brain, being important for the ATN  AD biomarker framework, implemented  in memory clinic routine, being a reference for evaluating new plasma biomarkers and following Aß monoclonal antibody treatment showing a marked reduction of amyloid plaques. Several neurodegenerative disorders are characterized by tauopathy, and Cryo-EM studies have convincingly demonstrated multiple tau isoforms. For visualizing of  3R/4R repeat tau  in AD the first generation of tau PET tracers such as 18F-flortaucipir, approved by FDA,  show off target binding and identifying tau at quite high levels of neuropathological change while the secondary tau PET tracers as 18F-MK6240, 18F-RO948, 18F-PI2620 demonstrate higher sensitivity to detect tau in MCI and at presymptomatic stages. A high discriminative property has been observed for AD versus other tauopathies and it can be expected that Tau PET might soon come into use in memory clinics. For primary tauopathies such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) new 4R selective Tau PET tracers are urgently needed, and research is ongoing. A growing interest in developing new PET tracers for reactive astrogliosis and microglia activation as well as new PET tracers for quantification  synaptic SV2A density and a-synuclein levels will be important tools for future multi-modal PET imaging studies providing new mechanistic  insights and for promising clinical praxis.

Affiliation: NVS,Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet,  Stockholm, Sweden

Keywords: Molecular  PET imaging, Multi-modal PET tracers, Imaging biomarkers, Clinical application

#16
Bernard Hanseeuw

Tau-PET imaging: From research data to Appropriate Use Criteria

Abstract: The first PET tracers specific for neurofibrillary tau tangles were developed a decade ago. Since then, tau-PET signal has consistently demonstrated strong association with cognitive performance, both measured concurrently and in the years following tau imaging. The spatial extension of tau pathology allows distinguishing between different clinical phenotypes of AD. However, this novel technique is not yet approved for clinical use in Europe. The clinical utility of tau-PET needs to be established, above and beyond fluid biomarkers and amyloid-PET that are both approved by EMA to confirm an AD diagnosis biologically. The talk will cover recent papers demonstrating the association of tau-PET with cognition and use clinical cases to illustrate utility beyond other available biomarkers. The conclusion would be a discussion with the audience about potential appropriate use criteria in the clinical setting.

Affiliation:

• Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
• Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Keywords: tau-PET, Alzheimer’s disease, cognition, diagnosis, prognosis

#17
Maura Malpetti

PET imaging of synaptic health across
neurodegenerative diseases

Abstract: The clinical and pathological heterogeneity across neurodegenerative diseases is a challenge for diagnoses and experimental medicine, calling for efficient biomarkers to stratify and monitor in clinical trials. Loss of synapses and their plasticity is an early and clinically-relevant feature across diseases. Positron emission tomography (PET) can be used to measure synaptic health and function. From early work with FDG to novel PET ligands for synaptic vesicle glycoprotein 2A, in vivo PET has been crucial to quantify and localise synaptic dysfunction and loss. The combination of PET markers for synaptic health with physiological and fluid markers of other pathological processes offers fundamental insights into neurodegenerative diseases, and provides biomarkers with clinical utility. These tools can facilitate the validation of preclinical models, and inform the design of new disease-modifying treatment strategies.

Affiliation: Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge CB2 0SZ, UK.

Keywords: synaptic health, PET, Alzheimer’s disease, frontotemporal lobar degeneration, SV2A

#18
Julien Lagarde

PET imaging of neuroinflammation in AD and potential implications in therapeutic trials

Abstract: In Alzheimer’s Disease (AD), chronic innate neuroinflammation mediated by microglia and astrocytes develops in the brain parenchyma in response to pathological aggregation of Ab and Tau species. Brain neuroinflammation can be investigated using positron emission tomography (PET) imaging of the 18-kDa translocator protein (TSPO), which is overexpressed by activated microglia. By using [¹⁸F]DPA-714 radioligand, PET studies have shown various temporal activation patterns among AD patients from the early stage, associated differentially with either detrimental (fast decliners) or neuroprotective (slow decliners) responses. The neuroinflammatory profile measured by [¹⁸F]DPA-714 binding may vary according to the patients themselves rather than the disease stage, and then progress differently over the course of the disease.

Interindividual profiles of brain neuroinflammatory response deserve to be considered in future trials with immunotherapy in order to (1) re-evaluate the choice of therapeutic targets so as not to target pathological proteins exclusively by administering antibodies, but by also considering the key role of both central neuroinflammation and central-peripheral immune crosstalk in AD pathogenesis, (2) refine patient stratification by further defining the inflammatory component, (3) define more accurate clinical outcomes and prognostic biomarkers that better reflect disease heterogeneity. Subject to further validation and development of specific tracers for different microglial subtypes, PET imaging could be included in this process, in association with potential peripheral immune biomarkers that have yet to be defined. It could be one of the tools used to select and adapt the treatment regimen for future immunotherapies, as well as to monitor target engagement.

Affiliation: ¹ Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte-Anne, F-75014, Paris, France

² Université Paris-Cité, F-75006 Paris, France

³ Université Paris-Saclay, BioMaps, Service Hospitalier Frédéric Joliot CEA, CNRS, Inserm, F-91401, Orsay, France

Keywords: neuroinflammation, microglia, PET imaging, immunotherapy

#19
Ruben Smith

LAlpha-synuclein PET imaging

Abstract: There has been a rapid development of biomarkers for diagnosing and staging of Neurodegenerative Diseases over the past decade. The most apparent advances have been made in imaging biomarkers, such as positron emission tomography (PET) tracers detecting neurofibrillary tau, as well as blood and cerebrospinal fluid biomarkers detecting phosphorylated subspecies of tau in Alzheimer’s Disease. But recently, promising methods have been developed for detecting α-synuclein in body fluids and biopsies using seed amplification assays, and initial PET studies have visualized α-synuclein aggregates in synucleinopathies such as multiple system atrophy (MSA).

This presentation aims to give an overview of recent developments in imaging biomarkers for α-synuclein in relation to neuronal Lewy body disease (Parkinson’s disease and Lewy body dementia) and MSA. The presentation will include recent findings and experiences using [¹⁸F]ACI-12589 from the Swedish BioFINDER study as well as data from the literature for other α-synuclein PET tracers under development. Challenges and pitfalls in tracer α-synuclein PET tracer development will be discussed as well as what requirements need to be met for an optimal α-synuclein PET tracer.

Affiliation: ¹ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden

² Memory Clinic, Skåne University Hospital, Malmö, Sweden.

Keywords: Alpha-synuclein, PET-imaging, biomarkers, Lewy body disease, Multiple system atrophy