The P2X(7) receptor tracer [C-11]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study

Purpose: The novel PET tracer [11C]SMW139 binds with high affinity to the P2X7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [11C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS. / Methods: Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [11C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion. / Results: The optimal model for describing [11C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (VT) and binding potential (BPND) in RRMS compared with HC in normal appearing brain regions. BPND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased VT was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional VT and BPND values. / Conclusions: This first in-man study demonstrated that uptake of [11C]SMW139 can be quantified with PET using BPND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer

Tau PET and relative cerebral blood flow in Dementia with Lewy bodies: A PET study

Purpose: Alpha-synuclein often co-occurs with Alzheimer’s disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. / Methods: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology(DLB-AD+). Receptor parametric mapping(cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. / Results: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p>0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p<0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p<0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stβ=0.72) and category fluency (stβ=0.69) tests. Lower parietal R1 was related to lower delayed (stβ=0.50) and immediate (stβ=0.48) recall, VOSP number location (stβ=0.70) and fragmented letters (stβ=0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stβ=0.61), all p<0.05. / Conclusion: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET

Multi-tracer model for staging cortical amyloid deposition using PET imaging

OBJECTIVE: To develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability. METHODS: 3027 subjects (1763 Cognitively Unimpaired (CU), 658 Impaired, 467 Alzheimer's disease (AD) dementia, 111 non-AD dementia, and 28 with missing diagnosis) from six cohorts (EMIF-AD, ALFA, ABIDE, ADC, OASIS-3, ADNI) who underwent amyloid PET were retrospectively included; 1049 subjects had follow-up scans. Applying dataset-specific cut-offs to global Standard Uptake Value ratio (SUVr) values from 27 regions, single-tracer and pooled multi-tracer regional rankings were constructed from the frequency of abnormality across 400 CU subjects (100 per tracer). The pooled multi-tracer ranking was used to create a staging model consisting of four clusters of regions as it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables and longitudinal cognitive decline were investigated. RESULTS: SUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices, then the associative, temporal and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of stage 0-4 subjects, respectively. Baseline stage predicted decline in MMSE (ADNI: N=867, F=67.37, p3000 subjects across cohorts and radiotracers, and detects pre-global amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive subjects

Neuroinflammation: From target selection to preclinical and clinical studies

Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis in neurological disorders and often serves as a prognostic marker for disease outcome. The underlying cellular and factorial heterogeneity represents an opportunity in the development of disease-modifying therapies. Molecular imaging of neuroinflammation (NI) may support the characterization of key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the multifactorial inflammatory response in vivo in animal models and patients. The characterization of the NI response by molecular imaging will (i) support early diagnosis and disease follow-up, (ii) guide (stereotactic) biopsy sampling, (iii) highlight the dynamic changes during disease pathogenesis in a noninvasive manner, (iv) help monitoring existing therapies, (v) support the development of novel NI-modifying therapies, and (vi) aid stratification of patients, according to their individual NI profile. This book chapter will review the basic principles of NI, recent developments and applications of novel molecular imaging targets, key considerations for the selection and development of imaging targets, as well as examples of successful clinical translation of NI imaging