Valerio Zenatti’s research while affiliated with Deutsches Zentrum für Neurodegenerative Erkrankungen and other places

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N -acetyl- l -leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.

Purpose Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in the brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated. Experimental Design We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n = 41), astrocytoma WHO grade 2 (n = 7), and healthy controls (n = 20) and compared TSPO-PET signals of the non-lesion (i.e., contralateral) hemisphere. Back-translation into syngeneic SB28 glioblastoma mice was used to characterize Pet alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain. Results Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions. Conclusions Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression.

Local therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults, indicating global involvement of the brain in this fatal disease. To study the impact of neuroinflammation distant of the primary tumor site on the clinical course of patients with glioblastoma, we performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma, glioma WHO 2 and healthy controls and compared signals of the non-lesion (i.e. contralateral) hemisphere. Back-translation in syngeneic glioblastoma mice was used to characterize PET alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain. Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epilepsy and poor prognosis independent of the tumor phenotype. Back-translation pinpointed myeloid cells as the source of TSPO-PET signal increases and revealed a complex immune signature comprised of joint myeloid cell activation and immunosuppression in distant brain regions. In brief, neuroinflammation within the contralateral hemisphere is associated with poor outcome in patients with newly diagnosed glioblastoma. TSPO-PET serves to detect patients with global neuroinflammation who may benefit from immunomodulatory strategies.