First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody.

With most of the T cells residing in the tissue, not the blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics is important for studying their role in immune response and memory. This study presents the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell biodistribution in humans. A 89Zr-labeled CD8-targeted minibody (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy individuals (N = 3) and coronavirus disease 2019 (COVID-19) convalescent patients (N = 5). Kinetic modeling results aligned with T cell-trafficking effects expected in lymphoid organs. Tissue-to-blood ratios from the first 7 hours of imaging were higher in bone marrow of COVID-19 convalescent patients compared to controls, with an increasing trend between 2 and 6 months after infection, consistent with modeled net influx rates and peripheral blood flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.

First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody.

With the majority of CD8+ T cells residing and functioning in tissue, not blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics in humans offers the means for studying their key role in adaptive immune response and memory. This study is the first report on using positron emission tomography (PET) dynamic imaging and compartmental kinetic modeling for in vivo measurement of whole-body biodistribution of CD8+ T cells in human subjects. For this, a 89Zr-labeled minibody with high affinity for human CD8 (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy subjects (N=3) and in COVID-19 convalescent patients (N=5). The high detection sensitivity, total-body coverage, and the use of dynamic scans enabled the study of kinetics simultaneously in spleen, bone marrow, liver, lungs, thymus, lymph nodes, and tonsils, at reduced radiation doses compared to prior studies. Analysis and modeling of the kinetics was consistent with T cell trafficking effects expected from immunobiology of lymphoid organs, suggesting early uptake in spleen and bone marrow followed by redistribution and delayed increasing uptake in lymph nodes, tonsils, and thymus. Tissue-to-blood ratios from the first 7 h of CD8-targeted imaging showed significantly higher values in the bone marrow of COVID-19 patients compared to controls, with an increasing trend between 2 and 6 months post-infection, consistent with net influx rates obtained by kinetic modeling and flow cytometry analysis of peripheral blood samples. These results provide the platform for using dynamic PET scans and kinetic modelling to study total-body immunological response and memory.

Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease.

Mutations in ß-amyloid (Aß) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Aß peptides production from APP. An antibody targeting Aß (aducanumab) was approved as an AD treatment; however, some Aß antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aß production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish-mutant neurons. Modest elevations of Aß, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aß. These data are consistent with the relative inefficacy of BACE1 and anti-Aß treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aß but rather by a long-term effect of elevated Aß concentrations.

A novel PRRT2 pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures.

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in PRRT2 (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel PRRT2 pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described PRRT2 pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel PRRT2 variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of PRRT2 in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of PRRT2 and the significance of this variant in regulating neural development and/or function.

Urban tree canopy and asthma, wheeze, rhinitis, and allergic sensitization to tree pollen in a New York City birth cohort.

BACKGROUND: Urban landscape elements, particularly trees, have the potential to affect airflow, air quality, and production of aeroallergens. Several large-scale urban tree planting projects have sought to promote respiratory health, yet evidence linking tree cover to human health is limited. OBJECTIVES: We sought to investigate the association of tree canopy cover with subsequent development of childhood asthma, wheeze, rhinitis, and allergic sensitization. METHODS: Birth cohort study data were linked to detailed geographic information systems data characterizing 2001 tree canopy coverage based on LiDAR (light detection and ranging) and multispectral imagery within 0.25 km of the prenatal address. A total of 549 Dominican or African-American children born in 1998-2006 had outcome data assessed by validated questionnaire or based on IgE antibody response to specific allergens, including a tree pollen mix. RESULTS: Tree canopy coverage did not significantly predict outcomes at 5 years of age, but was positively associated with asthma and allergic sensitization at 7 years. Adjusted risk ratios (RRs) per standard deviation of tree canopy coverage were 1.17 for asthma (95% CI: 1.02, 1.33), 1.20 for any specific allergic sensitization (95% CI: 1.05, 1.37), and 1.43 for tree pollen allergic sensitization (95% CI: 1.19, 1.72). CONCLUSIONS: Results did not support the hypothesized protective association of urban tree canopy coverage with asthma or allergy-related outcomes. Tree canopy cover near the prenatal address was associated with higher prevalence of allergic sensitization to tree pollen. Information was not available on sensitization to specific tree species or individual pollen exposures, and results may not be generalizable to other populations or geographic areas.