Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.

Background: The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates.

Changes in Functional Connectivity Relate to Modulation of Cognitive Control by Subthalamic Stimulation.

Subthalamic (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients not only improves kinematic parameters of movement but also modulates cognitive control in the motor and non-motor domain, especially in situations of high conflict. The objective of this study was to investigate the relationship between DBS-induced changes in functional connectivity at rest and modulation of response- and movement inhibition by STN-DBS in a visuomotor task involving high conflict. During DBS ON and OFF conditions, we conducted a visuomotor task in 14 PD patients who previously underwent resting-state functional MRI (rs-fMRI) acquisitions DBS ON and OFF as part of a different study.

Stress granules formation in HEI-OC1 auditory cells and in H4 human neuroglioma cells secondary to cisplatin exposure.

Stress granules (SGs) are highly dynamic micromolecular membraneless condensates that generate in cells subjected to stress. Formed from pools of untranslating messenger ribonucleoproteins (RNP), SGs dynamics constitute vital processes essential for cell survival. Here, we investigate whether established cytotoxic agents, such as the platinum-based chemotherapeutic agent cisplatin and the aminoglycoside antibiotic gentamicin, elicit SG formation in the House Ear Institute-Organ of Corti-1 (HEI-OC1) auditory cell line, H4 human neuroglioma cells and HEK-293T human embryonic kidney cells.

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 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.

Human induced pluripotent stem cells for live cell cycle monitoring and endogenous gene activation.

The fluorescence ubiquitination cell cycle inhibitor (FUCCI) has been introduced to monitor cell cycle activity in living cells, including human induced pluripotent stem cells (hiPSC) and derived cell types. We have recently developed hiPSC with stable expression of dCas9VPR for endogenous gene activation and a Citrine-tagged ACTN2 cell line to monitor sarcomere development and function in muscle cells. Here, we present dual and triple transgenic hiPSC lines developed by genomic integration of FUCCI with and without dCas9VPR into the ROSA26 and AAVS1 loci, respectively, in the previously introduced ACTN2-Citrine line.

Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa-Results of the HIT 2000 trial.

Background: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization, and biology in pediatric survivors of a posterior fossa tumor.

Methods: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic tool based on Cattell-Horn-Carroll's model for intelligence were analyzed.

Image-based dosimetry for [Ac]Ac-PSMA-I&T therapy and the effect of daughter-specific pharmacokinetics.

Purpose: Although Fr and Bi have sufficient gamma emission probabilities, quantitative SPECT after [Ac]Ac-PSMA-I&T therapy remains challenging due to low therapeutic activities. Furthermore, Fr and Bi may underlie a different pharmacokinetics due to alpha recoil. We conducted a quantitative SPECT study and a urine analysis to investigate the pharmacokinetics of Fr and Bi and the impact on image-based lesion and kidney dosimetry.

EANM practice guidelines for an appropriate use of PET and SPECT for patients with epilepsy.

Epilepsy is one of the most frequent neurological conditions with an estimated prevalence of more than 50 million people worldwide and an annual incidence of two million. Although pharmacotherapy with anti-seizure medication (ASM) is the treatment of choice, ~30% of patients with epilepsy do not respond to ASM and become drug resistant. Focal epilepsy is the most frequent form of epilepsy.

Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic variants.

Gene variants in are implicated to cause Noonan syndrome associated with a severe and early-onset hypertrophic cardiomyopathy. Mechanistically, deficiency results in accumulation of RAS GTPases and, as a consequence, in RAS-MAPK signaling hyperactivity, thereby causing the Noonan syndrome-associated phenotype. Despite its epidemiological relevance, pharmacological as well as invasive therapies remain limited.

Pineal anlage tumor: clinical and diagnostic features, and rationales for treatment.

Purpose: To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT).

Methods: Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases.

Results: Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports).

Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases.

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels.

The atypical antidepressant tianeptine confers neuroprotection against oxygen-glucose deprivation.

Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen-glucose deprivation (OGD) mimics key aspects of ischemic injury in vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD.

Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease.

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons.

Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization.

Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), the second most commonly occurring neurodegenerative disorder worldwide. We recently reported the development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface.

Neuropathology of incidental Lewy body & prodromal Parkinson's disease.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy.

Biodistribution and dosimetry for combined [Lu]Lu-PSMA-I&T/[Ac]Ac-PSMA-I&T therapy using multi-isotope quantitative SPECT imaging.

Purpose: Quantitative SPECT for patient-specific dosimetry is a valuable tool in the scope of radionuclide therapy, although its clinical application for Ac-based treatments may be limited due to low therapeutic activities. Therefore, the aim of this study was to demonstrate the feasibility of clinical quantitative low-count SPECT imaging during [Lu]Lu-PSMA-I&T/[Ac]Ac-PSMA-I&T treatment.

Methods: Eight prostate cancer patients (1000 MBq/8 MBq [Lu]Lu-PSMA-I&T/[Ac]Ac-PSMA-I&T) received a single-bed quantitative Lu/Ac SPECT/CT acquisition (1 h) at 24 h post treatment (high-energy collimator, 16 projections p.