Synaptic Loss in Multiple Sclerosis: A Systematic Review of Human Post-mortem Studies

Background: Gray matter pathology plays a central role in the progression of multiple sclerosis (MS). The occurrence of synaptic loss appears to be important but, to date, still poorly investigated aspect of MS pathology. In this systematic review, we drew from the recent knowledge about synaptic loss in human post-mortem studies.Methods: We conducted a systematic search with PubMed to identify relevant publications. Publications available from15 June 2021 were taken into account. We selected human post-mortem studies that quantitatively assessed the synapse number in MS tissue.Results: We identified 14 relevant publications out of which 9 reported synaptic loss in at least one investigated subregion. The most commonly used synaptic marker was synaptophysin; non-etheless, we found substantial differences in the methodology and the selection of reference tissue. Investigated regions included the cortex, the hippocampus, the cerebellum, the thalamus, and the spinal cord.Conclusion: Synaptic loss seems to take place throughout the entire central nervous system. However, the results are inconsistent, probably due to differences in the methodology. Moreover, synaptic loss appears to be a dynamic process, and thus the nature of this pathology might be captured using in vivo synaptic density measurements.

Morphogenesis of a complex glial niche requires an interplay between cellular growth and fusion

Neural stem cells (NSCs) are found in a tailored, intricate cellular microenvironment, the niche, which supports and regulates their activity. Whilst niche architecture is indissociable from its function, the morphogenetic aspects of niche development have been poorly explored. Here, we use the formation of the cortex glia (CG) network in Drosophila as a paradigm of acquisition of architectural complexity of a NSC niche. CG are essential for normal neurogenesis and build a reticular network spanning the entire central nervous system while encasing each NSC linage. We first show that individual CG cells grow tremendously to enwrap several NSC linages, ultimately covering and tiling the entire tissue. Several proliferative mechanisms, including endoreplication and mitosis, in part acytokinetic, support such growth and result in the formation of multinucleated, syncytial CG cells, that we call units. We then reveal that CG units are able to fuse to each other, resulting in the exchange of several subcellular compartments, such as membrane, cytoplasm and organelles. This process relies on well-known molecular players of cell fusion, involving cell surface communication molecules and actin regulators, while being atypical by its extent, dynamics and partial nature. Ultimately, the coordination in time and space of growth, proliferation and fusion mechanisms is required for the remarkable, multi-level architecture of the Drosophila NSC niche.

RADT-05. CLINICAL OUTCOMES OF PROTON CRANIOSPINAL IRRADIATION FOR PATIENTS WITH LEPTOMENINGEAL CARCINOMATOSIS

Leptomeningeal carcinomatosis (LC) is a devastating complication of metastatic tumors. Radiotherapy (RT) is integral to LC treatment, and proton craniospinal irradiation (CSI) may make RT more effective by targeting the entire central nervous system (CNS) compartment. We evaluated outcomes in patients treated with proton CSI for LC. We identified 56 patients treated with proton CSI for LC between 2018 and 2020 at our institution. Data on patient demographics, disease and treatment history, cerebrospinal fluid circulating tumor cells (CSF CTCs), and gene alterations were collected. Kaplan Meier analysis and Cox regression models were used to compare correlates with CNS time to progression (TTP), CNS progression-free survival (PFS) and overall survival (OS). Most patients had non-small cell lung cancer (NSCLC, n=27, 48%) or breast cancer (n=21, 38%). The median age was 58 (30-77), and median KPS was 80 (60-90). The median RT dose was 30Gy (25-36). The median follow-up was 12 months (1-22), with 26 (46%) patients alive at the last follow-up. Of 35 (63%) patients who progressed, 6 (11%) progressed in the CNS, 13 (23%) progressed systemically, and 16 (29%) progressed in both. The median TTP, PFS and OS was 8 months (1-21), 6 months (1-21) and 8 months (1-22), respectively. No difference in PFS (7 vs. 6 months, p=0.6) and OS (8 vs. 7 months, p=0.3) was observed between patients with NSCLC and breast cancer. Of patients alive at 3 months, 79% showed stable or improved functional status after CSI. Decreased CSF CTCs immediately post CSI had significantly improved PFS (8 vs. 5 months with no CTC decrease, HR=0.3, p=0.02). Lastly, we identified genetic correlates with survival outcomes. Proton CSI appears to be a promising treatment for LC in select patients, resulting in prolonged CNS disease control and survival. A randomized trial is currently underway to assess its efficacy prospectively.

Clinical trial of proton craniospinal irradiation for leptomeningeal metastases

Background Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. Methods We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS). Results We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment–related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5–13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months. Conclusion Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

CMET-21. A PHASE IB STUDY OF PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF SOLID TUMOR LEPTOMENINGEAL METASTASES

Leptomeningeal metastases (LM) is associated with limited survival and treatment options for patients with solid tumor malignancies. While focal radiotherapy is effective for local palliation, it lacks durability due to cerebrospinal fluid (CSF) tumor cells reseeding. Craniospinal irradiation (CSI) in contrast treats the entire central nervous system (CNS) compartment thus potentially improves disease control. We performed a phase IB study of proton CSI using 30CGE in 10 fractions for treating solid tumor LM (NCT03520504). The primary end point is dose-liming toxicity (DLT) within 1 month of treatment. Clinical outcomes and CSF circulating tumor cells (CTCs) by CellSearch® were evaluated. Overall (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Of the 24 patients enrolled, 4 were excluded from analysis: 3 did not complete treatment due to CNS or systemic disease progression (PD), and 1 completed treatment outside study window. The majority of patients had metastatic lung (55%) and breast (30%) malignancies. At this submission, the median follow-up was 2.8 months (0.5–9.4 months). No DLT was observed. Treatment-related grade 2+ toxicities were: fatigue (G2=43%), anorexia (G2=5%), anemia (G2=10%), thrombocytopenia (G3=5%, G2=10%), and leukopenia (G3=14%, G2=14%). Median survival is not reached with 17 patients (85%) alive with stable/improved LM including 2 with durable CNS control for >9 months, 1 patient alive with CNS and systemic PD at 3.7 months, 2 patients died at 3.6 and 5.1 months with CNS and systemic PD. At 3-month, OS and PFS were 100% and 90% (95% CI 100–72%), respectively. In the 13 patients with CSF CTCs evaluation, decreased quantifiable CTCs at 1-month after proton CSI correlated significantly with improved CNS PFS (log-rank p=0.014). These early findings suggest that proton CSI is a safe and potentially effective treatment for patients with solid tumor LM. CSF biomarkers assessment is needed to better elucidate predictors of response.

The Emerging Nature of Astrocyte Diversity

Astrocytes are morphologically complex, ubiquitous cells that are viewed as a homogeneous population tiling the entire central nervous system (CNS). However, this view has been challenged in the last few years with the availability of RNA sequencing, immunohistochemistry, electron microscopy, morphological reconstruction, and imaging data. These studies suggest that astrocytes represent a diverse population of cells and that they display brain area– and disease–specific properties and functions. In this review, we summarize these observations, emphasize areas where clear conclusions can be made, and discuss potential unifying themes. We also identify knowledge gaps that need to be addressed in order to exploit astrocyte diversity as a biological phenomenon of physiological relevance in the CNS. We thus provide a summary and a perspective on astrocyte diversity in the vertebrate CNS.

Engineering induction of singular neural rosette emergence within hPSC-derived tissues

Human pluripotent stem cell (hPSC)-derived neural organoids display unprecedented emergent properties. Yet in contrast to the singular neuroepithelial tube from which the entire central nervous system (CNS) develops in vivo, current organoid protocols yield tissues with multiple neuroepithelial units, a.k.a. neural rosettes, each acting as independent morphogenesis centers and thereby confounding coordinated, reproducible tissue development. Here, we discover that controlling initial tissue morphology can effectively (>80%) induce single neural rosette emergence within hPSC-derived forebrain and spinal tissues. Notably, the optimal tissue morphology for observing singular rosette emergence was distinct for forebrain versus spinal tissues due to previously unknown differences in ROCK-mediated cell contractility. Following release of geometric confinement, the tissues displayed radial outgrowth with maintenance of a singular neuroepithelium and peripheral neuronal differentiation. Thus, we have identified neural tissue morphology as a critical biophysical parameter for controlling in vitro neural tissue morphogenesis furthering advancement towards biomanufacture of CNS tissues with biomimetic anatomy and physiology.

Skull Base Dural Thickness and Relationship to Demographic Features: A Postmortem Study and Literature Review

Dural membrane is an important anatomic structure that surrounds and protects the entire central nervous system. Physical properties of the dura have many pathophysiological and therapeutic implications in cranial surgery, especially skull base disorders. The aim of this study is to investigate variation in skull base dural thickness and correlation with different demographic parameters. At the time of autopsy, the petrous apex dura with the underlying bone of 20 cadavers was harvested. Dural thickness was independently measured by two pathologists at the thinnest and thickest segments in the specimen. Correlational analyses were then performed to compare dural thickness with gender, age, neck circumference, height, weight, and body mass index (BMI). Mean, minimum, and maximum skull base dural thickness in our study was 0.36, 0.27, and 0.46 mm, respectively. Age demonstrated a negative correlation with dural thickness with significantly thinner dura in the older subjects, p = 0.01. There was a trend toward thinner dura in females that approached statistical significance, p = 0.06. No strong correlation could be found with body weight, height, neck circumference, or BMI. Our findings show a considerable intersubject and intrasubject variability in skull base dural thickness. Some demographic parameters also seem to impact dural thickness. Additional histological studies are needed for better understanding of the pathophysiological mechanisms pertaining to the tensile properties of the dural membrane.

Management of Myelomeningocele: Eight Years Experience in Dhaka Medical College and Hospital

Introduction: Myelomeningocele is a single most common congenital malformation that affects the entire central nervous system and because of extensive internal CNS involvement, its management remains controversial. Proper management of affected children can lead to a meaningful and productive life, and poorly managed cases of myelomeningocele can be a devastating obstacle not only for patient but also for the patient’s family.Materials and methods: This was a descriptive study, started in January, 2007 and completed in December 2014 in the Department of Pediatric Surgery and Department of Neurosurgery of Dhaka Medical College & Hospital (DMCH).The medical records of 42 children with myelomeningocele operated at our center were reviewed retrospectively. The surgical & medical management protocol used for different sites of myelomeningocele was studied.Results: The age of most of the patients at the time of myelomeningocele repair was between 45 days to 60 days; however, children with ruptured myelomeningocele were consistently repaired early after controlling infection. In our study, 16 patients (38.1%) of myelomeningocele with hydrocephalus were operated for medium pressure ventriculoperitoneal (VP) shunt first, and then repair after 7 days to 10 days. VP shunt was done 7 days after repair of myelomeningocele in 11 patients (26.19%), who developed hydrocephalus postoperatively. All 8 patients with ruptured myelomeningocele (19.05%) were treated for ventriculitis first, then by repair. Seven patients (16.67%) with intact lesion were repaired between 4 weeks to 8 weeks of age. Complications including CSF leak, wound infection, wound dehiscence, paraplegia, autonomic incontinence, shunt infection and malfunction after repair of myelomeningocele occurred in 27 patients (64.29%). Six patients (14.29%) died during treatment protocol. All the patients were followed up postoperatively for 6 months to 1 year.Conclusion: Surgical intervention with or without VP shunt of patients with myelomeningocele produced good results.J. Paediatr. Surg. Bangladesh 5(2): 54-57, 2014 (July)

Abstract 085: Role of Suppressor of Cytokines Signaling 3 (Socs3) in Modulating Chronic Metabolic and Cardiovascular Effects of Leptin

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of leptin signaling. Hypothalamic SOCS3 is upregulated in obese animals fed a high-fat diet and has been suggested to contribute to development of resistance to leptin’s anorexic effects. In this study we determined whether deletion of SOCS3 in the entire central nervous system (CNS) amplifies the chronic anorexic and blood pressure (BP) effects of physiological increases in plasma leptin in mice fed a normal diet. SOCS3 flox/flox -Nestin-cre mice were generated by breeding SOCS3 flox/flox with Nestin-cre mice. BP and heart rate (HR) were recorded by telemetry, and oxygen consumption (VO 2 ) was monitored by indirect calorimetry in 22-week-old SOCS3 flox/flox -Nestin-cre (n=4) and control mice (SOCS3 flox/flox , n=4). Compared to controls SOCS3 flox/flox -Nestin-cre mice were lighter (30±1 vs 33±1 g) and normoglycemic (124±7 vs 146±10 mg/dl), consumed less food (3.0±0.4 vs 3.6±0.2 g/day) and had similar VO 2 (77±6 vs 73±3 ml/kg/min). SOCS3 flox/flox -Nestin-cre mice had similar MAP (103±3 vs 107±3 mmHg) but higher HR (666±15 vs 602±17 bpm) compared to control mice. Chronic leptin infusion greatly reduced food in SOCS3 flox/flox -Nestin-cre (46±3 vs 35±4%) and increased MAP (15±3 vs 7±2 mmHg) and VO2 (18±3 vs 14±2%) compared to control mice. No significant changes were observed in HR in either group. Leptin infusion significantly reduced blood glucose levels in both groups (124±7 to 97±7 vs 146±10 to 105±7 mg/dl). These results indicate that SOCS3 deletion in the entire CNS reduces body weight and food intake, and amplifies leptin’s effect on appetite and blood pressure and also suggest the SOCS3 signaling attenuates the chronic actions of leptin on blood pressure as well as appetite regulation even in non-obese mice fed a normal diet. (NHLBI-PO1HL51971, NIGMS P20GM104357 and AHA SDG5680016)