Neuroinflammation is a key pathologic hallmark of numerous neurologic diseases, however, its exact role in vivo is yet to be fully understood. PET imaging enables investigation, quantification, and tracking of different neuroinflammation biomarkers in living subjects longitudinally. One such biomarker that has been imaged extensively using PET is translocator protein 18 kDa (TSPO). Although imaging TSPO has yielded valuable clinical data linking neuroinflammation to various neurodegenerative diseases, considerable limitations of TSPO PET have prompted identification of other more cell-specific and functionally relevant biomarkers. This review analyzes the clinical potential of available and emerging PET biomarkers of innate and adaptive immune responses, with mention of exciting future directions for the field.

The medial temporal lobe is one of the most well-studied brain regions affected by Alzheimer's disease (AD). Although the spread of neurofibrillary pathology in the hippocampus throughout the progression of AD has been thoroughly characterized and staged using histology and other imaging techniques, it has not been precisely quantified in vivo at the subfield level using simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI). Here, we investigate alterations in metabolism and volume using [ 18 F]fluoro-deoxyglucose (FDG) and simultaneous time-offlight (TOF) PET/MRI with hippocampal subfield analysis of AD, mild cognitive impairment (MCI), and healthy subjects. We found significant structural and metabolic changes within the hippocampus that can be sensitively assessed at the subfield level in a small cohort. While no significant differences were found between groups for whole hippocampal SUVr values (p = 0.166), we found a clear delineation in SUVr between groups in the dentate gyrus (p = 0.009). Subfield analysis may be more sensitive for detecting pathological changes using PET-MRI in AD compared to global hippocampal assessment. The medial temporal lobe (MTL), which includes the hippocampus and adjacent entorhinal and perirhinal cortices, is critical to memory formation and retrieval and well known to be involved in most forms of Alzheimer's disease (AD) 1. Neurodegeneration within the MTL thus leads to memory impairments in both AD and amnestic mild cognitive impairment (MCI) 2. This neurodegeneration results in atrophy that can be measured using structural MRI 3 and a reduction in metabolism of [ 18 F]fluoro-deoxyglucose (FDG) in PET imaging 4. The hippocampus is divided into subfields distinct in cytoarchitecture, connectivity, and function in both health and disease 5-9. From external to internal, relevant MTL subregions include perirhinal cortex (PRC), entorhinal cortex (ERC), subiculum (SUB), cornu ammonis fields 1-4 (CA1-4), and dentate gyrus (DG) (Fig. 1). ERC connects the neocortex to the hippocampus by primarily projecting to DG, which in turn projects to CA3, then to CA1 and to SUB, and back to ERC 10. AD neurofibrillary pathology spreads through the hippocampus as disease progresses. In the earliest stages of AD, neurofibrillary pathology is limited to the transentorhinal (part of PRC) and entorhinal cortices 11. As AD progresses, hippocampal involvement begins with neuron loss and tau tangles in CA1/2, progresses to CA3/4 and then to SUB and DG 12,13. AD symptoms are strongly correlated with the extent of hippocampal neurofibrillary involvement 14,15. Thus, image-based subfield measurements could be non-invasive biomarkers for diagnosis and staging of AD. Several MRI studies have shown that hippocampal subfield morphological measurements detect sensitive differences between AD, MCI, and healthy subjects. Some studies have found that CA1 and DG volume is reduced in AD subjects compared to MCI subjects 14,16 and may be a biomarker of presymptomatic AD 17-23. Development...

Purpose: Motion artifact limits the clinical translation of high-field MR. We present an optical prospective motion correction system for 7 Tesla MRI using a custombuilt, within-coil camera to track an optical marker mounted on a subject. Methods: The camera was constructed to fit between the transmit-receive coils with direct line of sight to a forehead-mounted marker, improving upon prior mouthpiece work at 7 Tesla MRI. We validated the system by acquiring a 3D-IR-FSPGR on a phantom with deliberate motion applied. The same 3D-IR-FSPGR and a 2D gradient echo were then acquired on 7 volunteers, with/without deliberate motion and with/ without motion correction. Three neuroradiologists blindly assessed image quality.In 1 subject, an ultrahigh-resolution 2D gradient echo with 4 averages was acquired with motion correction. Four single-average acquisitions were then acquired serially, with the subject allowed to move between acquisitions. A fifth single-average 2D gradient echo was acquired following subject removal and reentry. Results: In both the phantom and human subjects, deliberate and involuntary motion were well corrected. Despite marked levels of motion, high-quality images were produced without spurious artifacts. The quantitative ratings confirmed significant improvements in image quality in the absence and presence of deliberate motion across both acquisitions (P < .001). The system enabled ultrahigh-resolution visualization of the hippocampus during a long scan and robust alignment of serially acquired scans with interspersed movement. Conclusion: We demonstrate the use of a within-coil camera to perform optical prospective motion correction and ultrahigh-resolution imaging at 7 Tesla MRI. The 1662 | DIGIACOMO et Al.

Parkinson's disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO)-positron emission tomography (PET) is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo, however it is yet to be fully explored in PD. Herein we investigate the utility of TSPO-PET, in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1) -a novel biomarker of proinflammatory innate immune cells -for detecting innate immune responses in the 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic neuron degeneration. Methods: C57/BL6J and TREM1-knockout mice were stereotaxically injected with 6-OHDA in the left striatum; control mice were saline-injected. At day 7 or 14 post-surgery, mice were administered 18 F-GE-180, 64 Cu-TREM1-mAb or 64 Cu-Isotype control-mAb and imaged by PET/CT. Ex vivo autoradiography (ARG) was performed to obtain high resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death and quantitative PCR and flow cytometry were completed to assess levels of target in the brain. Results: PET/CT images of both tracers showed elevated signal within the striatum of 6-OHDA-injected mice compared to those injected with saline. ARG afforded higher resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-OHDA-compared to salineinjected mice at both 7-and 14-days post-toxin. Interestingly, 18 F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-OHDA mice, whereas 64 Cu-TREM1-mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain. Conclusion: TSPO-and TREM1-PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential.

Introduction: Alzheimer's disease (AD) is the most common form of dementia, characterized primarily by abnormal aggregation of two proteins, tau and amyloid beta. We assessed tau pathology and white matter connectivity changes in subfields of the hippocampus simultaneously in vivo in AD.Methods: Twenty-four subjects were scanned using simultaneous time-of-flight 18 F-PI-2620 tau positron emission tomography/3-Tesla magnetic resonance imaging and automated segmentation. Results:We observed extensive tau elevation in the entorhinal/perirhinal regions, intermediate tau elevation in cornu ammonis 1/subiculum, and an absence of tau elevation in the dentate gyrus, relative to controls. Diffusion tensor imaging showed parahippocampal gyral fractional anisotropy was lower in AD and mild cognitive impairment compared to controls and strongly correlated with early tau accumulation in the entorhinal and perirhinal cortices.Discussion: This study demonstrates the potential for quantifiable patterns of 18 F-PI2620 binding in hippocampus subfields, accompanied by diffusion and volume metrics, to be valuable markers of AD.