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β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT= 0.412 ± 0.196 vs. βA= 0.142 ± 0.123, p< 0.001; AD-CBS: βT= 0.385 ± 0.176 vs. βA= 0.131 ± 0.186, p= 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT= 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of ɣ-aminobutyric acid type A (GABAA) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABAAreceptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the field of immune therapy in treating relapsed and refractory B cell malignancies. Despite remarkable progress, CD19 CAR-T cell therapy is associated with major side effects, most significantly are cytokine-release syndrome and neurotoxicity. Of note, 40-60% of patients receiving CD19 CAR-T cells suffer from severe neurotoxicity termed immune cell-associated-neurotoxicity-syndrome (ICANS), which remains a major obstacle limiting their therapeutic efficacy. Several pre-clinical reports using xenograft mouse models have been published to address ICANS, however, they do not fully recapitulate the clinical scenario. Identifying and targeting the molecular mediators of neurotoxicity could help ameliorate ICANS induced by CD19 CAR-T cells.

A 69-year-old woman presented with progressive dysarthria and cognitive deficits. On MRI, a T2-hyperintense, non–contrast-enhancing lesion was found in the left precentral area. 18F-FET and 18F-FDG PET scans revealed faint amino acid uptake and glucose hypometabolism of the lesion. To assess a neuroinflammatory component, TSPO PET with 18F-GE-180 was performed, where tracer uptake markedly exceeded the T2-hyperintense areas. Histology derived from a stereotactic biopsy findings confirmed John Cunningham virus–associated progressive multifocal leukoencephalopathy. This case underlines that TSPO PET comprises distinct imaging advantages over other established radioligands such as 18F-FET and 18F-FDG in progressive multifocal leukoencephalopathy.

68Ga-DOTATOC PET/CT is a reliable imaging modality in the diagnosis and therapy planning of symptomatic meningiomas. We present a case of a 74-year-old woman where a supposed SSTR-positive sphenoid wing meningioma turned out to be a breast cancer metastasis. Our case shows that dural metastases from breast cancer might represent a clinical pitfall in 68Ga-DOTATOC PET/CT.

PET using 68Ga-labeled somatostatin receptor (SSTR) ligands adds significant information in meningioma patients. 18F-SiTATE is a novel, 18F-labeled SSTR-targeting peptide with remarkable imaging properties. Here, we present a 72-year-old woman with falx meningioma and transosseous extension. 18F-SiTATE PET/CT was performed 12 months after the previous 68Ga-DOTATOC PET/CT with comparable quantitative uptake and very good spatial resolution. So far, the widespread use of SSTR ligands for NET and meningioma imaging is hampered by cost-intensive 68Ge/68Ga generators, low activity amounts, lower spatial resolution, and short half-life. 18F-SiTATE might foster widespread use of SSTR ligands, overcoming the shortcomings of 68Ga-labeled ligands.

The aim is to explore the concept of photopenic defects in newly diagnosed glioma patients with the 2 widely used 11C-MET and 18F-FDOPA PET amino acid tracers. Thirty-two 11C-MET and 26 18F-FDOPA PET scans with amino acid PET-negative gliomas were selected in this European multicentric study. Of these gliomas, 16 11C-MET and 10 18F-FDOPA PET scans with photopenic defects were identified, exhibiting lower mean tumor-to-background ratio as compared with isometabolic gliomas (P< 0.001). Gliomas with photopenic defects had no different progression-free survival than isometabolic gliomas in the whole population (P= 0.40), but shorter progression-free survival in the subgroup of World Health Organization grade II IDH-mutant astrocytomas (35 vs 68 months; P= 0.047).

A 25-year-old man presented with headache and intracranial pressure symptoms. On MRI, an intracranial lesion was detected in the right thalamus with exophytic growth into the third ventricle and inhomogeneous contrast enhancement without necrosis. Dual amino acid (18F-FET) and TSPO (18F-GE-180) PET imaging showed high tumor-to-background ratios in both scans and a short time-to-peak in 18F-FET uptake dynamics. Biopsy revealed a diffuse midline glioma, H3K27M-mutant (WHO grade IV), a novel entity in the 2016 WHO classification with poor clinical outcome. Our case shows that the highly aggressive features of this tumor entity can be visualized in vivo by both PET modalities.

PET targeting the translocator protein (TSPO) expression is an interesting approach to detect neuroinflammation, as TSPO is upregulated in activated macrophages and microglia. Considering the variable pathophysiology of multiple sclerosis (MS) variants, we compare TSPO PET using 18F-GE-180 in 3 different demyelinating diseases of the central nervous system: relapsing-remitting MS, tumefactive MS, and Baló’s concentric sclerosis. Visualization of neuroinflammation and its PET patterns in addition to MRI may contribute to accurate distinction and monitoring of central nervous system demyelination.

A 43-year-old woman with suspected recurrence of atypical meningioma World Health Organization grade II presented extensive intracranial lesions with high 68Ga-DOTATATE uptake. Moreover, numerous 68Ga-DOTATATE–positive bone, lung, and liver lesions were seen. For final diagnosis, biopsies taken from a lung lesion revealed distant metastases of the atypical meningioma. This case underlines the high diagnostic power of 68Ga-DOTATATE PET/CT for the staging of meningioma even beyond cerebral or spinal lesions; in case of distant lesions in patients with known meningioma, differential diagnosis should also contain metastases despite their rare occurrence. Moreover, this case emphasizes radioligand therapy especially in metastatic meningioma.

PET targeting the translocator protein (TSPO) represents an interesting approach for glioma visualization, as TSPO is highly expressed in tumor cells. We present a 32-year-old man with recurrent glioblastoma after multimodal treatment. PET with the novel TSPO ligand 18F-GE-180 was performed after reirradiation. Here, the previously reirradiated tumor showed a remaining circular TSPO expression. Moreover, cerebrospinal fluid dissemination was detected by a high focal uptake at the right lateral and at the fourth ventricle, whereas only a faint contrast enhancement was present in MRI. This case demonstrated the diagnostic potential of TSPO-PET for glioma imaging by visualizing even minimal disease burden.