Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome.

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 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 in 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.

Spindle-locked ripples mediate memory reactivation during human NREM sleep.

Memory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation. Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of slow oscillation - spindle activity coincided with the read-out of experimentally induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be correlated with the identification of memory reactivation during non-rapid eye movement sleep. Our findings establish ripples as key-oscillation for sleep-related memory reactivation in humans and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.

Electrophysiological signatures of veridical head direction in humans.

Information about heading direction is critical for navigation as it provides the means to orient ourselves in space. However, given that veridical head-direction signals require physical rotation of the head and most human neuroimaging experiments depend upon fixing the head in position, little is known about how the human brain is tuned to such heading signals. Here we adress this by asking 52 healthy participants undergoing simultaneous electroencephalography and motion tracking recordings (split into two experiments) and 10 patients undergoing simultaneous intracranial electroencephalography and motion tracking recordings to complete a series of orientation tasks in which they made physical head rotations to target positions. We then used a series of forward encoding models and linear mixed-effects models to isolate electrophysiological activity that was specifically tuned to heading direction. We identified a robust posterior central signature that predicts changes in veridical head orientation after regressing out confounds including sensory input and muscular activity. Both source localization and intracranial analysis implicated the medial temporal lobe as the origin of this effect. Subsequent analyses disentangled head-direction signatures from signals relating to head rotation and those reflecting location-specific effects. Lastly, when directly comparing head direction and eye-gaze-related tuning, we found that the brain maintains both codes while actively navigating, with stronger tuning to head direction in the medial temporal lobe. Together, these results reveal a taxonomy of population-level head-direction signals within the human brain that is reminiscent of those reported in the single units of rodents.

Evaluation of surgical treatment strategies and outcome for cerebral arachnoid cysts in children and adults.

OBJECTIVE: The best treatment strategies for cerebral arachnoid cysts (CAC) are still up for debate. In this study, we present CAC management, outcome data, and risk factors for recurrence after surgical treatment, focusing on microscopic/endoscopic approaches as compared to minimally invasive stereotactic procedures in children and adults. METHODS: In our single-institution retrospective database, we identified all patients treated surgically for newly diagnosed CAC between 2000 and 2022. Microscopic/endoscopic surgery (ME) aimed for safe cyst wall fenestration. Stereotactic implantation of an internal shunt catheter (STX) to drain CAC into the ventricles and/or cisterns was used as an alternative procedure in patients aged ≥ 3 years. Treatment decisions in favor of ME vs. STX were made by interdisciplinary consensus. The primary study endpoint was time to CAC recurrence (TTR). Secondary endpoints were outcome metrics including clinical symptoms and MR-morphological analyses. Data analysis included subdivision of the total cohort into three distinct age groups (AG1, < 6 years; AG2, 6-18 years; AG3, ≥ 18 years). RESULTS: Sixty-two patients (median age 26.5 years, range 0-82 years) were analyzed. AG1 included 15, AG2 10, and AG3 37 patients, respectively. The main presenting symptoms were headache and vertigo. In AG1 hygromas, an increase in head circumference and thinning of cranial calvaria were most frequent. Thirty-five patients underwent ME and 27 STX, respectively; frequency did not differ between AGs. There were two (22.2%) periprocedural venous complications in infants (4- and 10-month-old) during an attempt at prepontine fenestration of a complex CAC, one with fatal outcome in a 10-month-old boy. Other complications included postoperative bleeding (2, 22.2%), CSF leaks (4, 44.4%), and meningitis (1, 11.1%). Overall, clinical improvement and significant volume reduction (p = 0.008) were seen in all other patients; this did not differ between AGs. Median follow-up for all patients was 25.4 months (range, 3.1-87.1 months). Recurrent cysts were seen in 16.1%, independent of surgical procedure used (p = 0.7). In cases of recurrence, TTR was 7.9 ± 12.7 months. Preoperative ventricular expansion (p = 0.03), paresis (p = 0.008), and age under 6 years (p = 0.03) were significant risk factors for CAC recurrence in multivariate analysis. CONCLUSIONS: In patients suffering from CAC, both ME and STX can improve clinical symptoms at low procedural risk, with equal extent of CAC volume reduction. However, in infants and young children, CAC are more often associated with severe clinical symptoms, stereotactic procedures have limited use, and microsurgery in the posterior fossa may bear the risk of severe venous bleeding.

Risk-benefit analysis of surgical treatment strategies for cystic craniopharyngioma in children and adolescents.

Objective: Treatment strategies for craniopharyngiomas are still under debate particularly for the young population. We here present tumor control and functional outcome data after surgical treatment focusing on stereotactic and microsurgical procedures for cystic craniopharyngiomas in children and adolescents. Methods: From our prospective institutional database, we identified all consecutive patients less than 18 years of age who were surgically treated for newly-diagnosed cystic craniopharyngioma between, 2000 and, 2022. Treatment decisions in favor of stereotactic treatment (STX) or microsurgery were made interdisciplinary. STX included aspiration and/or implantation of an internal shunt catheter for permanent cyst drainage. Microsurgery aimed for safe maximal tumor resections. Study endpoints were time to tumor recurrence (TTR) and functional outcome including ophthalmological/perimetric, endocrinological, and body-mass index (BMI) data. Results: 29 patients (median age 9.9 yrs, range 4-18 years) were analyzed. According to our interdisciplinary tumor board recommendation, 9 patients underwent stereotactic treatment, 10 patients microsurgical resection, and 10 patients the combination of both. Significant volume reduction was particularly achieved in the stereotactic (p=0.0019) and combined subgroups (p<0.001). Improvement of preoperative visual deficits was always achieved independent of the applied treatment modality. Microsurgery and the combinational treatment were associated with higher rates of postoperative endocrinological dysfunction (p<0.0001) including hypothalamic obesity (median BMI increase from 17.9kg/m2 to 24.1kg/m2, p=0.019). Median follow-up for all patients was 93.9 months (range 3.2-321.5 months). Recurrent tumors were seen in 48.3% and particularly concerned patients after initial combination of surgery and STX (p=0.004). In here, TTR was 35.1 ± 46.9 months. Additional radiation therapy was found indicated in 4 patients to achieve long-lasting tumor control. Conclusion: In children and adolescents suffering from predominantly cystic craniopharyngiomas, stereotactic and microsurgical procedures can improve clinical symptoms at low procedural risk. Microsurgery, however, bears a higher risk of postoperative endocrine dysfunction. A risk-adapted surgical treatment concept may have to be applied repeatedly in order to achieve long-term tumor control even without additional irradiation.

Efficacy and safety of cysto-ventricular catheter implantation for space-occupying cysts arising from glioma and brain metastasis: a retrospective study.

BACKGROUND: Cysto-ventricular catheters (CVC) have emerged as promising treatment option for cystic craniopharyngioma and arachnoid cysts, but their effectiveness in treating cysts originating from glioma or brain metastasis (BM) remains limited. This study aimed to analyze the efficacy of CVC in patients with glioma and BM as well as procedure-associated morbidity. METHODS: This single-center retrospective study included all patients treated with CVC placement for acquired space-occupying cysts deriving from previously treated glioma or BMs between 1/2010 and 12/2021. RESULTS: A total of 57 patients with a median age of 47 years (IQR 38-63) were identified. Focal neurological deficits were the predominant symptoms in 60% of patients (n = 34), followed by cephalgia in 14% (n = 8), and epileptic seizures in 21.1% (n = 12). Accurate CVC placement was achieved in all but one case requiring revision surgery due to malposition. Three months after CVC implantation, 70% of patients showed symptomatic improvement. Multivariate logistic regression analysis identified the development of space-occupying cysts later in the course of the disease (OR 1.014; p = 0.04) and a higher reduction of cyst-volume postoperatively (OR 1.055; p = 0.05) were significant predictors of postoperative symptomatic improvement following CVC placement. Local cyst recurrence was observed in three cases during follow-up MRI after an average time of 5 months (range 3-9 months). Further complications included secondary malresorptive hydrocephalus in three cases and meningeosis neoplastica in one patient. CONCLUSIONS: Stereotactic implantation of CVC is an efficient treatment option for patients suffering from symptomatic space-occupying cysts from BMs or glioma, independently from their CNS WHO grade. However, a vigilant approach is crucial regarding potential complications and treatment failures.