3D quantitative assessment of response to fractionated stereotactic radiotherapy and single-session stereotactic radiosurgery of vestibular schwannoma.

OBJECTIVES: To determine clinical outcome of patients with vestibular schwannoma (VS) after treatment with fractionated stereotactic radiotherapy (FSRT) and single-session stereotactic radiosurgery (SRS) by using 3D quantitative response assessment on MRI. MATERIALS: This retrospective analysis included 162 patients who underwent radiation therapy for sporadic VS. Measurements on T1-weighted contrast-enhanced MRI (in 2-year post-therapy intervals: 0-2, 2-4, 4-6, 6-8, 8-10, 10-12 years) were taken for total tumour volume (TTV) and enhancing tumour volume (ETV) based on a semi-automated technique. Patients were considered non-responders (NRs) if they required subsequent microsurgical resection or developed radiological progression and tumour-related symptoms. RESULTS: Median follow-up was 4.1 years (range: 0.4-12.0). TTV and ETV decreased for both the FSRT and SRS groups. However, only the FSRT group achieved significant tumour shrinkage (p < 0.015 for TTV, p < 0.005 for ETV over time). The 11 NRs showed proportionally greater TTV (median TTV pre-treatment: 0.61 cm(3), 8-10 years after: 1.77 cm(3)) and ETV despite radiation therapy compared to responders (median TTV pre-treatment: 1.06 cm(3); 10-12 years after: 0.81 cm(3); p = 0.001). CONCLUSION: 3D quantification of VS showed a significant decrease in TTV and ETV on FSRT-treated patients only. NR had significantly greater TTV and ETV over time. KEY POINTS: Only FSRT not GK-treated patients showed significant tumour shrinkage over time. Clinical non-responders showed significantly less tumour shrinkage when compared to responders. 3D volumetric assessment of vestibular schwannoma shows advantages over unidimensional techniques.

Conceptual design of a GEM (gas electron multiplier) based gas Cherenkov detector for measurement of 17 MeV gamma rays from T(D, γ)5He in magnetic confinement fusion plasmas.

The only method for assessing the fusion power throughput of a deuterium-tritium (DT) reactor presently relies on determining the absolute number of 14 MeV neutrons produced in the DT plasma. An independent method, developed and investigated during the recent DT campaign at the Joint European Torus, is based on the absolute counting of 17 MeV gamma rays produced by the competing T(D, γ)5He reaction that features a very weak branching ratio (about 3-6 × 10-6) when compared to the main T(D, n)4He reaction. The state-of-the-art spectrometer used for gamma-ray measurements in magnetic confinement fusion plasmas is LaBr3(Ce) scintillator detectors, although they require significant neutron shielding to extract a relatively weak gamma-ray signal from a much more abundant neutron field. A better approach relies on a gamma-ray detector that is intrinsically insensitive to neutrons. We have advanced the design of a gamma-ray counter based on the Cherenkov effect for gamma-rays whose energy exceeds 11 MeV, optimized to work in the neutron-rich environment of a steady-state, magnetically confined fusion plasma device. The gamma-rays interact with an aluminum window and extract electrons that move into the radiator emitting photons via the Cherenkov effect. Since the Cherenkov light consists of few photons (25 on average) in the far UV band (100-200 nm), a pre-amplifier is required to transport the photons to the neutron-shielded location, which may be a few meters away, where the readout elements of the detector, either a silicon or standard photomultiplier tube, are placed. The present work focuses on the development of a scintillating GEM (Gas Electron Multiplier) based pre-amplifier that acts as a Cherenkov photon pre-amplifier and wavelength shifter. This paper presents the result of a set of Garfield++ simulations developed to find the optimal GEM working parameters. A photon gain of 100 is obtained by biasing a single GEM foil to 1 kV.

Upgrades to the gamma ray imager on DIII-D enabling access to high flux hard x-ray measurements during the runaway electron plateau phase (invited).

The Gamma Ray Imager (GRI) is a pinhole camera providing 2D imaging of MeV hard x-ray (HXR) bremsstrahlung emission from runaway electrons (REs) over the poloidal cross section of the DIII-D tokamak. We report a series of upgrades to the GRI expanding the access to RE scenarios from the diagnosis of a trace amount of REs to high flux HXR measurements during the RE plateau phase. We present the implementation of novel gamma ray detectors based on LYSO and YAP crystals coupled to multi-pixel photon counters, enabling a count rate in excess of 1 MHz. Finally, we highlight new insights into the RE physics discovered during the current quench and RE plateau phase experiments as the result of these upgrades.

Role of neutron attenuators for gamma-ray measurements in deuterium-tritium magnetic confinement plasmas.

The Joint European Torus (JET) is the only tokamak in the world able to operate in Deuterium-Tritium (DT) plasmas. A successful DT experimental campaign, the DTE2, has recently been carried out, providing unique opportunities for studying both physics and technological aspects. In particular, it allowed us to investigate and benchmark the solutions adopted to attenuate the significant 14 MeV neutron flux, needed to enable high-resolution gamma-ray spectroscopy measurements on a tokamak. While in inertial confinement experiments, gamma-rays and neutrons are discriminated through time-of-flight techniques; in magnetic confinement experiments, the neutron attenuators are a key element to allow gamma-ray measurements in order to reestablish the 1 × 105 to 1 background to signal ratio. In this paper, the role of the reference neutron attenuators at JET, based on LiH, has been analyzed and described.

A new dedicated signal processing system for gamma-ray spectrometers in high power deuterium-tritium plasma scenarios in tokamaks.

The most performant deuterium-tritium (DT) plasma discharges realized by the Joint European Torus (JET) tokamak in the recent DT campaign have produced neutron yields on the order of 1018 n/s. At such high neutron yields, gamma-ray spectroscopy measurements with scintillators are challenging as events from the neutron-induced background often dominate over the signal, leading to a significant fraction of pileup events and instability of the photodetector gain along with the consequent degradation of the reconstructed spectrum. Here, we describe the solutions adopted for the tangential lanthanum bromide spectrometer installed at JET. A data acquisition system with free streaming mode digitization capabilities for the entire duration of the discharge has been used to solve dead-time related issues and a data reconstruction code with pileup recovery and photodetector gain drift restoration has been implemented for off-line analysis of the data. This work focuses on the acquired data storage and parsing, with a detailed explanation of the pileup recovery and gain drift restoration algorithms.

A high-resolution neutron spectroscopic camera for the SPARC tokamak based on the Jet European Torus deuterium-tritium experience.

Dedicated nuclear diagnostics have been designed, developed, and built within EUROFUSION enhancement programs in the last ten years for installation at the Joint European Torus and capable of operation in high power Deuterium-Tritium (DT) plasmas. The recent DT Experiment campaign, called DTE2, has been successfully carried out in the second half of 2021 and provides a unique opportunity to evaluate the performance of the new nuclear diagnostics and for an understanding of their behavior in the record high 14 MeV neutron yields (up to 4.7 × 1018 n/s) and total number of neutrons (up to 2 × 1019 n) achieved on a tokamak. In this work, we will focus on the 14 MeV high resolution neutron spectrometers based on artificial diamonds which, for the first time, have extensively been used to measure 14 MeV DT neutron spectra with unprecedented energy resolution (Full Width at Half Maximum of ≈1% at 14 MeV). The work will describe their long-term stability and operation over the DTE2 campaign as well as their performance as neutron spectrometers in terms of achieved energy resolution and high rate capability. This important experience will be used to outline the concept of a spectroscopic neutron camera for the SPARC tokamak. The proposed neutron camera will be the first one to feature the dual capability to measure (i) the 2.5 and 14 MeV neutron emissivity profile via the conventional neutron detectors based on liquid or plastics scintillators and (ii) the 14 MeV neutron spectral emission via the use of high-resolution diamond-based spectrometers. The new opportunities opened by the spectroscopic neutron camera to measure plasma parameters will be discussed.

Fusion product measurements by nuclear diagnostics in the Joint European Torus deuterium-tritium 2 campaign (invited).

A new deuterium-tritium experimental, DTE2, campaign has been conducted at the Joint European Torus (JET) between August 2021 and late December 2021. Motivated by significant enhancements in the past decade at JET, such as the ITER-like wall and enhanced auxiliary heating power, the campaign achieved a new fusion energy world record and performed a broad range of fundamental experiments to inform ITER physics scenarios and operations. New capabilities in the area of fusion product measurements by nuclear diagnostics were available as a result of a decade long enhancement program. These have been tested for the first time in DTE2 and a concise overview is provided here. Confined alpha particle measurements by gamma-ray spectroscopy were successfully demonstrated, albeit with limitations at neutron rates higher than some 1017 n/s. High resolution neutron spectroscopy measurements with the magnetic proton recoil instrument were complemented by novel data from a set of synthetic diamond detectors, which enabled studies of the supra-thermal contributions to the neutron emission. In the area of escaping fast ion diagnostics, a lost fast ion detector and a set of Faraday cups made it possible to determine information on the velocity space and poloidal distribution of the lost alpha particles for the first time. This extensive set of data provides unique information for fundamental physics studies and validation of the numerical models, which are key to inform the physics and scenarios of ITER.

Gene therapy of experimental brain tumors using neural progenitor cells.

Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they may travel along the white matter, like neoplastic cells, and engraft stably into the brain. Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas. Here, we transferred the gene for interleukin-4 into C57BL6J mouse primary neural progenitor cells and injected those cells into established syngeneic brain glioblastomas. This led to the survival of most tumor-bearing mice. We obtained similar results by implanting immortalized neural progenitor cells derived from Sprague-Dawley rats into C6 glioblastomas. We also documented by magnetic resonance imaging the progressive disappearance of large tumors, and detected 5-bromodeoxyuridine-labeled progenitor cells several weeks after the injection. These findings support a new approach for gene therapy of brain tumors, based on the grafting of neural stem cells producing therapeutic molecules.

Novel compact hard x-ray spectrometer with MCps counting rate capabilities for runaway electron measurements on DIII-D.

A novel compact spectrometer optimized for the measurement of hard x rays generated by runaway electrons is presented. The detector is designed to be installed in the fan-shaped collimator of the gamma-ray imager diagnostic at the DIII-D tokamak. The spectrometer is based on a 1 × 1 cm2 cerium doped yttrium aluminum perovskite scintillator crystal coupled with a silicon photomultiplier. The detector dynamic energy range is in excess of 10 MeV, with an energy resolution of ∼10% at 661.7 keV. The fast detector signal (≈70 ns full width at half maximum) allows for operation at counting rates in excess of 1 MCps. The gain stability of the system can be monitored in real time using a light-emitting diode embedded in the instrument. The detector is expected to be deployed in the forthcoming DIII-D runaway electron experimental campaign.

A new tangential gamma-ray spectrometer for fast ion measurements in deuterium and deuterium-tritium plasmas of the Joint European Torus.

A new tangential gamma-ray spectrometer has been developed for fast ion measurements in deuterium and deuterium-tritium plasmas of the Joint European Torus (JET). The instrument is based on a LaBr3 crystal with a photo-multiplier tube and replaces a pre-existing bismuth germanate detector, providing enhanced energy resolution and a counting rate capability in the MHz range. The line of sight is equipped with a LiH attenuator, which reduces the background due to 14 MeV neutron interactions with the crystal by more than two orders of magnitude and enables the observation of gamma-ray emission from confined α particles in JET deuterium-tritium plasmas. Thanks to its tangential line of sight, the detector can distinguish co- and counter-passing ions. The performance of the instrument is demonstrated through the results of recent JET fast ion experiments in deuterium plasmas.

First spatially resolved measurements of the D-3He α-particle source with the upgraded JET gamma-ray camera.

The Joint European Torus (JET) gamma-ray camera has been recently upgraded with the installation of new gamma-ray detectors, based on LaBr3(Ce) scintillation crystals, which add spectroscopic capability to the existing system allowing measurements with good energy resolution (5% at 0.622 MeV), a dynamic range from hundreds of keV up to about 30 MeV, and high counting rate capabilities of MCps. First gamma-ray measurements during the C38 campaign of the JET have been successfully carried out, in particular, in D-3He plasmas from three-ion ion cyclotron resonance heating experiments, where the detection of 16.4 MeV γ-rays from D + 3He → γ + 5Li reactions with the gamma-ray camera upgrade allowed determining the spatial profile of alpha particles born in D + 3He fusion reactions.

Action versus animal naming fluency in subcortical dementia, frontal dementias, and Alzheimer's disease.

Accumulating evidence indicates action naming may rely more on frontal-subcortical circuits, and noun naming may rely more on temporal cortex. Therefore, noun versus action fluency might distinguish frontal and subcortical dementias from cortical dementias primarily affecting temporal and/or parietal cortex such as Alzheimer's disease (AD). We hypothesized patients with subcortical dementia, e.g., normal pressure hydrocephalus (NPH) and patients with dementias predominantly affecting frontal cortex, e.g., behavioral variant frontotemporal dementia (bv-FTD) and progressive nonfluent aphasia (PNFA) have more difficulty on action fluency versus noun fluency (e.g., animal naming). Patients with AD, who have temporo parietal cortical dysfunction, should have more difficulty on noun versus verb fluency. A total of 234 participants, including healthy controls (n = 20) and patients diagnosed with NPH (n =144), AD (n = 33), bv-FTD (n = 22) or PNFA (n =15) were administered animal fluency, action fluency, and letter fluency tasks, and the Mini-Mental State Examination (MMSE, to control for dementia severity). NPH and bv-FTD/PNFA patients had significantly higher MMSE scores and animal fluency than AD patients (after adjusting for age), but their action fluency tended to be lower than in AD. Only NPH and bvFTD/PNFA patients showed significantly lower action verb than animal fluency. Results provide novel evidence that action naming relies more on frontal-subcortical circuits while noun naming relies more on temporoparietal cortex, indicating action verb fluency may be more sensitive than noun fluency, particularly for detecting frontal-subcortical dysfunction.

High-Resolution MRI for Evaluation of Ventriculostomy Tubes: Assessment of Positioning and Proximal Patency.

BACKGROUND AND PURPOSE: Imaging evaluation of ventriculostomy tubes, despite the frequency of malfunction, has remained inadequate due to the absence of a systematic way of assessing the catheter itself. In this retrospective review, we assessed the utility of high-resolution 3D MR imaging techniques, including CISS and volumetric interpolated breath-hold examination sequences, in the evaluation of ventriculostomy catheters. MATERIALS AND METHODS: We performed a retrospective review of 23 clinical MR imaging cases of shunted hydrocephalus spanning a 3-year period, all depicting ventriculostomy catheters. The MR imaging examinations included isotropic CISS and volumetric interpolated breath-hold examination sequences performed with and without contrast. These were independently evaluated by 2 neuroradiologists with respect to the catheter course, side hole position, relationship of the side holes to the ventricles, patency, and the presence or absence of intraluminal debris. RESULTS: The catheter tip was best seen on isotropic CISS sequences reformatted in an oblique plane, and side holes were visualized as CSF signal defects along the catheter wall in 10/23 (43%) cases. The relationship of the catheter side holes to the ventricles was seen in 47% of cases and was best visualized on the coronal CISS sequences. Catheter patency was confirmed in 12/23 (52%) cases, while the other 48% were notable for T2 hypointense filling defects compatible with luminal obstruction. Enhancement of some of these filling defects on imaging is suggestive of choroid plexus ingrowth rather than debris. CONCLUSIONS: High-resolution 3D MR imaging using isotropic CISS sequences allows systematic evaluation of catheter positioning, patency, and potential etiologic differentiation of filling defects when shunt dysfunction is suspected.

Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.

Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. Restoring wild-type huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD.

Development of gamma ray spectrometer with high energy and time resolutions on EAST tokamak.

A new gamma ray spectrometer with high energy and time resolutions has been developed and installed on the EAST tokamak to study fast ion and runaway electron behaviors. The spectrometer is based on a LaBr3(Ce) scintillator detector and a fully digital data acquisition system that is based on a digitizer with digital pulse processing algorithms. The energy resolution of the spectrometer is about 3.9% at 662 keV, and the spectrometer can operate stably at a counting rate as high as 1 MHz, monitored by using a light emitting diode monitoring system. The measured gamma ray spectrum is simulated based on Geant4 and unfolded with the high-resolution boosted Gold deconvolution algorithm, aiming at reconstructing the energy distribution functions of fast ions and runaway electrons.

Normal pressure hydrocephalus: long-term outcome after shunt surgery.

BACKGROUND/OBJECTIVE: Little is known about the long-term clinical course and management of patients with normal pressure hydrocephalus (NPH) treated by cerebrospinal fluid (CSF) shunting. METHODS: We retrospectively reviewed records of 55 patients diagnosed with idiopathic NPH (INPH) and treated with CSF shunts, all of whom were followed for more than 3 years after the original shunt surgery. At each annual follow-up visit, the patient was assessed by Folstein Mini Mental State Examination, detailed clinical evaluation of gait and assessment of headache, cognition, gait or urination, as assessed by the patient and relatives. RESULTS: The mean duration of follow-up was 5.9+/-2.5 years. There was an overall sustained improvement among all symptoms. Gait showed the highest maintenance of improvement over baseline (83% at 3 years and 87% at the last analysed follow-up of 7 years), cognition showed intermediary improvement (84% and 86%, respectively), and urinary incontinence showed the least improvement (84% and 80%, respectively). Fifty-three percent of patients required shunt revisions. Indications for revision included shunt malfunction (87%), infection (10%) and change of shunt configuration (3%). Overall, 74% revisions resulted in clinical improvement. CONCLUSIONS: Clinical improvement of patients with NPH can be sustained for 5-7 years in some patients with NPH, even if shunt revision surgery is needed multiple times. With earlier diagnosis and treatment of NPH and the increasing lifespan of the ageing population, the need for long-term follow-up after shunt surgery for NPH may be greater than it was in the past. Monitoring, identification and treatment of shunt obstruction is a key management principle.

Shc signaling in differentiating neural progenitor cells.

Previously we found that the availability of ShcA adapter is maximal in neural stem cells but that it is absent in mature neurons. Here we report that ShcC, unlike ShcA, is not present in neural stem/progenitor cells, but is expressed after cessation of their division and becomes selectively enriched in mature neurons. Analyses of its activity in differentiating neural stem/progenitor cells revealed that ShcC positively affects their viability and neuronal maturation via recruitment of the PI3K-Akt-Bad pathway and persistent activation of the MAPK pathway. We suggest that the switch from ShcA to ShcC modifies the responsiveness of neural stem/progenitor cells to extracellular stimuli, generating proliferation (with ShcA) or survival/differentiation (with ShcC).

Natural History of Endoscopic Third Ventriculostomy in Adults: Serial Evaluation with High-Resolution CISS.

BACKGROUND AND PURPOSE: Endoscopic third ventriculostomy is a well-accepted treatment choice for hydrocephalus and is used most frequently with a known impediment to CSF flow between the third ventricle and basal cisterns. However, there are scarce data on the imaging evolution of the defect in the floor of the third ventricle and how this affects patency rates and clinical outcomes. The purpose of this study was to assess whether, and how, the endoscopic third ventriculostomy defect changes in size with time. MATERIALS AND METHODS: All high-resolution endoscopic third ventriculostomy protocol MRIs performed between 2009 through 2014 were retrospectively identified. Two fellowship-trained neuroradiologists, blinded to clinical information, independently reviewed all retrospective cases. RESULTS: A total of 98 imaging studies were included from 34 patients. The average change in the area throughout the studied period was 0.02 mm2/day (7.5 mm2/year), with a higher increase in size noted in the first 3 postsurgical months, with a gradual decrease in the degree of defect-size change. Use of the NICO Myriad device was correlated with the area of the endoscopic third ventriculostomy defect on the last follow-up, demonstrating a larger final defect size in patients in whom the surgical technique included debridement of the endoscopic third ventriculostomy defect walls with the NICO Myriad device (28.21 versus 11.25 mm, P < .05). CONCLUSIONS: High-resolution MR imaging with sagittal CISS images is useful in the postoperative evaluation of endoscopic third ventriculostomies. Such findings may prove useful in determining the optimal duration of follow-up with MR imaging of patients who have undergone endoscopic third ventriculostomy.

Does the Presence or Absence of DESH Predict Outcomes in Adult Hydrocephalus?

BACKGROUND AND PURPOSE: The DESH (disproportionately enlarged subarachnoid-space hydrocephalus) pattern of "tight high-convexity and medial subarachnoid spaces, and enlarged Sylvian fissures with ventriculomegaly" is used to determine which patients undergo an operation for adult hydrocephalus at many centers. Our aim was to review adult hydrocephalus cases when DESH has not been a criterion for an operation to determine the prevalence of DESH among the cohort and compare the surgical outcomes in the presence or absence of DESH. MATERIALS AND METHODS: A retrospective cohort study was conducted at a single institution (Johns Hopkins Hospital) to include patients surgically treated for adult hydrocephalus between 2003 and 2014 drawn from a data base of patients who had undergone standardized hydrocephalus protocol MR imaging. Preoperative imaging was reviewed by 2 blinded neuroradiologists to characterize the presence of DESH. Preoperative and postoperative clinical symptomatology was recorded. Frequencies were compared using the Fisher exact test, and nonparametric means were compared using the Mann-Whitney U Test. RESULTS: One hundred thirty-three subjects were identified and included (96 DESH absent, 37 DESH present). Shunting led to significant improvement in gait and urinary and cognitive symptoms for the overall cohort and for patients with and without DESH (P < .05). The Fisher exact test did not demonstrate any significant differences in either gait or urinary or cognitive symptom improvement between patients with or without DESH (P > .05). CONCLUSIONS: The current study demonstrated symptom improvement in patients with adult hydrocephalus following shunting, with no significant differences between subjects with and without DESH. Thus, shunt insertion for patients with adult hydrocephalus should not rely solely on the presence of preoperative DESH findings.

Development of a new compact gamma-ray spectrometer optimised for runaway electron measurements.

A new compact gamma-ray spectrometer was developed in order to optimise the measurement of bremsstrahlung radiation emitted from runaway electrons in the MeV range. The detector is based on a cerium doped lutetium-yttrium oxyorthosilicate (LYSO:Ce) scintillator coupled to a silicon photomultiplier and is insensitive to magnetic fields. A dedicated electronic board was developed to optimise the signal readout as well as for online control of the device. The detector combines a dynamic range up to 10 MeV with moderate energy non-linearity, counting rate capabilities in excess of 1 MHz, and an energy resolution that extrapolates to a few % in the MeV range, thus meeting the requirements for its application to runaway electron studies by bremsstrahlung measurements in the gamma-ray energy range.