Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation.

Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients.

BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients. PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and -146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients. RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P = 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant. CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.

Cognitive outcome as part and parcel of clinical outcome in brain tumor surgery.

Although validated tools (neuropsychological tests, patient reported outcomes, mood and psychological profile) were first introduced many years ago in clinical practice, the impact of the tumor itself on patient cognition has not been extensively studied. Furthermore, while outcome research is evolving in an attempt to adapt the use of different tools to the preoperative and postoperative phases, the standard guidelines for evaluating outcome after brain surgery, by neurological examination and complication assessment, are frequently neglected in the current literature. This article attempts to provide an appraisal of the evidence for the impact of surgical treatment on cognitive function of brain tumor patients within the context of general outcome.

Multishell Diffusion MRI-Based Tractography of the Facial Nerve in Vestibular Schwannoma.

BACKGROUND AND PURPOSE: Tractography of the facial nerve based on single-shell diffusion MR imaging is thought to be helpful before surgery for resection of vestibular schwannoma. However, this paradigm can be vitiated by the isotropic diffusion of the CSF, the convoluted path of the facial nerve, and its crossing with other bundles. Here we propose a multishell diffusion MR imaging acquisition scheme combined with probabilistic tractography that has the potential to provide a presurgical facial nerve reconstruction uncontaminated by such effects. MATERIALS AND METHODS: Five patients scheduled for vestibular schwannoma resection underwent multishell diffusion MR imaging (b-values = 0, 300, 1000, 2000 s/mm2). Facial nerve tractography was performed with a probabilistic algorithm and anatomic seeds located in the brain stem, cerebellopontine cistern, and internal auditory canal. A single-shell diffusion MR imaging (b-value = 0, 1000 s/mm2) subset was extrapolated from the multishell diffusion MR imaging data. The quality of the facial nerve reconstruction based on both multishell diffusion MR imaging and single-shell diffusion MR imaging sequences was assessed against intraoperative videos recorded during the operation. RESULTS: Single-shell diffusion MR imaging-based tractography was characterized by failures in facial nerve tracking (2/5 cases) and inaccurate facial nerve reconstructions displaying false-positives and partial volume effects. In contrast, multishell diffusion MR imaging-based tractography provided accurate facial nerve reconstructions (4/5 cases), even in the presence of ostensibly complex patterns. CONCLUSIONS: In comparison with single-shell diffusion MR imaging, the combination of multishell diffusion MR imaging-based tractography and probabilistic algorithms is a more valuable aid for surgeons before vestibular schwannoma resection, providing more accurate facial nerve reconstructions, which may ultimately improve the postsurgical patient's outcome.

Multi-option therapy vs observation for small acoustic neuroma: hearing-focused management.

The current treatment options for acoustic neuromas (AN) - observation, microsurgery and radiotherapy - should assure no additional morbidity on cranial nerves VII and VIII. Outcomes in terms of disease control and facial function are similar, while the main difference lies in hearing. From 2012 to 2016, 91 of 169 patients (54%) met inclusion criteria for the present study, being diagnosed with unilateral, sporadic, intrameatal or extrameatal AN up to 1 cm in the cerebello-pontine angle; the remaining 78 patients (46%) had larger AN and were all addressed to surgery. The treatment protocol for small AN included observation, translabyrinthine surgery, hearing preservation surgery (HPS) and radiotherapy. Hearing function was assessed according to the Tokyo classification and the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) classification. Sixty-one patients (71%) underwent observation, 19 (22%) HPS and 6 (7%) translabyrinthine surgery; 5 patients were lost to follow-up. Median follow-up was 25 months. In the observation group, 24.6% of patients abandoned the wait-and-see policy for an active treatment; the risk of switching from observation to active treatment was significant for tumour growth (p = 0.0035) at multivariate analysis. Hearing deteriorated in 28% of cases without correlation with tumour growth; the rate of hearing preservation for classes C-D was higher than for classes A-B (p = 0.032). Patients submitted to HPS maintained an overall preoperative hearing class of Tokyo and AAO-HNS in 63% and 68% of cases, respectively. Hearing preservation rate was significantly higher for patients presenting with preoperative favourable conditions (in-protocol) (p = 0.046). A multi-option management for small AN appeared to be an effective strategy in terms of hearing outcomes.

Cognitive Rehabilitation in Patients with Gliomas and Other Brain Tumors: State of the Art.

Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years.

Spontaneous involution of diffuse fibrous dysplasia of paranasal sinuses.

We report the case of a 25-year-old patient, diagnosed at age 10, with diffuse fibrous dysplasia of the paranasal sinuses, an extremely rare idiopathic condition. This diagnosis is possible only by cerebral computed tomography (CT), cerebral and anterior skull base magnetic resonance imaging (MRI), and histopathology. Surgical treatment is common. This boy had mild symptoms: moderate headache in the morning that did not affect his daily activity, and rhinitis, partially responsive to medication. The neurologic examination was abnormal. Radiographs, CT, and MRI showed a diffuse mass in the paranasal sinuses which had a histopathological diagnosis of fibrous dysplasias. The family refused to refer the patient to surgery. The boy has been monitored annually for 15 years. He has remained asymptomatic without headache since age 11, with normal, general and neurologic examinations. Serial MRIs showed a spontaneous partial involution of the mass.

Novel characteristics of glutamate-induced cell death in primary septohippocampal cultures: relationship to calpain and caspase-3 protease activation.

Studies examined the phenotypic characteristics of glutamate-induced cell death and their relationship to calpain and caspase-3 activation. Cell viability was assessed by fluorescein diacetate and propidium iodide staining and lactate dehydrogenase release. Calpain and caspase-3 activity was inferred from signature proteolytic fragmentation of alpha-spectrin. Characterization of cell death phenotypes was assessed by Hoechst 33258 and DNA fragmentation assays. Exposure of septohippocampal cultures to 1.0, 2.0, and 4.0 mmol/L glutamate induced a dose-dependent cell death with an LD50 of 2.0 mmol/L glutamate after 24 hours of incubation. Glutamate treatment induced cell death in neurons and astroglia and produced morphological alterations that differed from necrotic or apoptotic changes observed after maitotoxin or staurosporine exposure, respectively. After glutamate treatment, cell nuclei were enlarged and eccentrically shaped, and aggregated chromatin appeared in a diffusely speckled pattern. Furthermore, no dose of glutamate produced evidence of internucleosomal DNA fragmentation. Incubation with varying doses of glutamate produced calpain and caspase-3 activation. Calpain inhibitor II (N-acetyl-Leu-Leu-methionyl) provided protection only with a narrow dose range, whereas carbobenzoxy-Asp-CH2-OC(O)-2,6-dichlorobenzene (Z-D-DCB; pan-caspase inhibitor) and MK-801 (N-methyl-D-aspartate receptor antagonist) were potently effective across a wider dose range. Cycloheximide did not reduce cell death or protease activation.

Behavioral deficits following experimental subarachnoid hemorrhage in the rat.

To characterize some of the short-term and long-term functional consequences of subarachnoid hemorrhage (SAH) in rats, we employed a battery of well-characterized tests for assessment of acute and chronic behavioral and neurologic performances. Three groups of 10 rats (blood injected, mock CSF injected and sham-operated controls) were studied. During the acute stage, simple nonpostural somatomotor reflexes (pinna and corneal reflexes), simple postural responses (paw flexion, tail flexion, and head support), startle response, and postural functions (righting reflex) did not differ significantly between the experimental groups. Assessments of body weight, beam walking ability, and beam balancing revealed significant disturbances in blood-injected rats. This work demonstrates that this single-hemorrhage rodent model of SAH is associated with the induction of enduring neurologic and behavioral deficits. Because of the significant interspecies difference, a direct extrapolation of our results to humans may not be appropriate. However, we suggest that the observed behavioral and neurologic changes may parallel those seen in humans after SAH. Results reported here further confirm the rat model of SAH as a viable laboratory instrument for the study of the pathophysiology of SAH and provide normative values for the evaluation of new treatment modalities.

Effect of experimental subarachnoid hemorrhage on CSF eicosanoids in the rat.

A simple and inexpensive experimental model of subarachnoid hemorrhage (SAH) was developed in the rat. Based on accumulating data indicating the important role of arachidonic acid metabolites in the etiology of delayed cerebral vasospasm, we investigated changes induced by SAH on cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2), F2 alpha (PGF2 alpha), and thromboxane B2 (TXB2). SAH was produced by the cisternal injection of blood via percutaneous suboccipital puncture. SAH rats (n = 200) were injected with 300 microliters of fresh autologous arterial blood; Control rats (n = 100) received the same volume of mock CSF. In 60 additional animals, no injections were made. To follow the changes induced by SAH on both the spectrum and time course of CSF eicosanoids, cisternal CSF samples were collected under basal conditions, 6, 12, and 36 after cisternal injection. PGE2, PGF2 alpha, and TXB2 were assayed in aliquots of CSF obtained by pooling samples from each experimental group. Eicosanoids were assayed using radioimmunoassay techniques. Arterial spasm was verified in parallel groups of SAH and control rats by comparison of the angiographic diameters of the basilar arteries (BA) and middle cerebral arteries (MCA) to that of the stapedial artery. CSF levels of all three eicosanoids were significantly higher in the SAH groups compared to both noninjected and mock-CSF injected control rats. These increases in concentrations of eicosanoids were accompanied by a decrease in the mean vascular diameter (77.5-82.0% of control) on day 2 following cisternal injection. We conclude that marked elevations of spasmogenic eicosanoids in the CSF are associated with experimental SAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional changes in spinal cord glucose metabolism in a rat model of painful neuropathy.

Spinal cord patterns of metabolic activity in a model of neuropathic pain were assessed in unanesthetized rats by the [14C]-2-deoxyglucose (2-DG) technique. Rats used in this procedure had demonstrable thermal hyperalgesia ipsilateral to sciatic nerve ligation and ipsilateral hindpaws that were lifted in a guarded position. The latter indicated possible spontaneous pain. Sciatic nerve ligation produced significant increases in glucose utilization in the dorsal and ventral horns of both sides, with greater activity present on the ipsilateral as compared to the contralateral side. Peak activity was in laminae V-VI, a region involved in nociceptive processing. Thus, a chronic increase in neuronal activity in these regions may reflect spontaneous neuropathic pain.

Effect of intracarotid injection of iopamidol on local cerebral glucose utilization in rat brain.

We assessed, by means of the [14C]-2-deoxy-D-glucose autoradiography method, the effect of intracarotid injection of a nonionic, low-osmolar contrast medium (iopamidol) on local cerebral glucose utilization in the rat brain. Contrast medium was injected at 20 degrees C and at 37 degrees C, and the relative changes in local cerebral glucose utilization were measured. At 20 degrees C the viscosity of the contrast agent was about twice that of the same solution at 37 degrees C, and resulted in a statistically significant increase in local cerebral glucose utilization in the hemisphere ipsilateral to the side of intracarotid infusion. Saline control studies showed that the metabolic change was not related to either the solution temperature or the osmolality. These findings suggest that increased viscosity of a contrast medium may contribute to its neurotoxic effects during cerebral angiography, hence emphasizing the importance of preheating contrast material to avoid adverse reactions.

Monitoring of brain tissue pressure with a fiberoptic device.

Continuous monitoring of brain tissue pressure can now be achieved with intracerebral placement of fiberoptic microtransducers. This study was undertaken to test the safety, accuracy, and reliability of this relatively new type of intracranial pressure (ICP) monitoring. Initially, the fiberoptic device was compared with a concurrently functioning intraventricular catheter in 18 patients. The results from the two methods corresponded closely over a wide range of pressures, and the correlation coefficient approached 1.0. Subsequently, this monitor was used for routine measurement of ICP in a series of almost 200 neurosurgical patients at risk of intracranial hypertension. The tracings showed good wave forms and consistent absolute values of ICP. No instances of hemorrhage, mechanical failure, or other complications were associated with this monitor, except one case of infection, which was not directly attributable to the device per se. When bilateral intraparenchymal pressures were recorded in patients with unilateral mass lesions, significant transitory pressure differentials between the ipsilateral and contralateral sides were documented. It is concluded that monitoring intraparenchymal pressure with the fiberoptic device offers safe and reliable ICP recordings for routine neurosurgical practice. In patients with unilateral masses, ICP should be measured in close proximity to the lesion.

Does lamina terminalis fenestration reduce the incidence of chronic hydrocephalus after subarachnoid hemorrhage?

OBJECTIVE: The incidence of chronic hydrocephalus requiring cerebrospinal fluid shunting was analyzed for a prospective series of 52 consecutive patients with ruptured cerebral aneurysms who underwent fenestration of the lamina terminalis during early microsurgical aneurysm repair. We hypothesized that, by creating an anterior ventriculocisternostomy, fenestration of the lamina terminalis would facilitate cerebrospinal fluid dynamics and decrease the risk of subsequent hydrocephalus. METHODS: Patients were enrolled according to the following criteria: 1) age more than 40 years; 2) admission Hunt and Hess Grade 2 to 4; 3) initial subarachnoid hemorrhage severity of Fisher Grade 3 or 4; and 4) early microsurgical repair of an anterior circulation aneurysm. RESULTS: The mortality rate in this series was 9.6%. Of the 47 surviving patients, 32 (68%) were discharged with a Glasgow Outcome Scale score of 5, 10 (21%) with a Glasgow Outcome Scale score of 4, and 5 (11%) with a Glasgow Outcome Scale score of 3. The follow-up period ranged from 12 to 60 months. Chronic hydrocephalus was radiographically and clinically evident in 3.8% of the total population. Shunt surgery was performed for two patients who exhibited symptoms resulting from hydrocephalus, corresponding to 4.2% of the surviving patients. CONCLUSION: Estimates from the most recently published studies indicate that an incidence of chronic post-subarachnoid hemorrhage hydrocephalus (requiring shunt surgery) of 15 to 20% is representative for an average contemporary population of patients with aneurysmal subarachnoid hemorrhage. The lower incidence of chronic hydrocephalus observed in this series possibly reflects the favorable effect of lamina terminalis fenestration on cerebrospinal fluid dynamics.

Chronic encapsulated intracerebral hematoma: contribution of thallium-201 single photon emission computed tomography in preoperative diagnosis: case report.

OBJECTIVE AND IMPORTANCE: Chronic encapsulated intracerebral hematoma is a fairly rare clinical entity. This unique lesion is peculiar for its clinical onset, formation of a capsule, and progressive enlargement. The mechanism for capsule formation and self-perpetuating expansion still remains uncertain, as well as the causal relationship with vascular malformations. Because of their pseudotumoral course and misleading neuroradiological features, these lesions can be misdiagnosed preoperatively as cerebral neoplasms. CLINICAL PRESENTATIONS: A 62-year-old man was referred with a 2-month history of generalized tonicoclonic seizures. There was no history of head injury or arterial hypertension. The results of a neurological examination were normal. Computed tomographic scans revealed a slightly hyperdense roundish area in the right parietotemporal region with ring-like enhancement after contrast medium injection, moderate mass effect, and perifocal low attenuation. With the provisional diagnosis of astrocytoma, the patient was admitted for a craniotomy. Before surgery, a thallium-201 single photon emission computed tomographic study was performed, which showed no abnormal uptake of the tracer, raising significant doubt regarding the presumptive diagnosis of a tumor. INTERVENTION: Intraoperative findings revealed a hematoma, with a well-demarcated, thick, fibrous-elastic capsule. There was evidence of repeated intracapsular hemorrhages. The lesion was totally removed, and the patient recovered fully. No other pathological findings, including vascular malformations, were noted. CONCLUSION: Chronic encapsulated intracerebral hematomas probably occur more frequently than the limited number of reported cases would indicate. This case represents a realistic clinical problem-solving setting in with thallium-201 single photon emission computed tomography was used because of its capacity for functional tumor detection and differential diagnosis.

Benign intracranial hypertension without papilledema: case report.

An obese young man presented the typical features of benign intracranial hypertension (BIH), including raised intracranial pressure. Despite elevated intracranial pressure, papilledema did not develop. The syndrome resolved after medical treatment and, on examination 6 months later, the patient was normal. The absence of papilledema in this case is discussed together with data available from the literature.

Blood-brain barrier permeability changes after experimental subarachnoid hemorrhage.

Basic mechanisms underlying cerebrovascular permeability responses to subarachnoid hemorrhage (SAH) are still to be defined in detail. Previous investigations examining the occurrence of blood-brain barrier (BBB) breakdown after SAH in the experimental setting have yielded conflicting results. In a rat model of SAH, we assessed BBB changes by means of the quantitative [14C]-alpha-aminoisobutyric acid technique. Experiments were carried out on the second day post-SAH. In blood-injected rats [14C]-alpha-aminoisobutyric acid transport across the BBB increased significantly in cerebral cortices and cerebellar gray matter, averaging 1.3 to 1.5 times control values. The present data indicate that SAH induces well-defined changes in BBB function, possibly involved in the pathogenesis of post-SAH cerebral dysfunction in humans. Results reported here have also potential clinical implications for the management of aneurysm patients.

Effect of whole brain radiation on local cerebral glucose utilization in the rat.

We assessed, by means of the [14C]-2-deoxy-D-glucose autoradiography method, the effect of whole-brain x-radiation on local cerebral glucose utilization in the rat brain. Animals were exposed to conventional fractionation (200 +/- 4 cGy/day, 5 days/week; total dose, 4000 cGy). Metabolic experiments were made 2 to 3 weeks after completion of the radiation exposure. In comparison with control and sham-irradiated animals, cerebral metabolic activity was diffusely decreased after irradiation. Statistically significant decreases in metabolic activity were observed in 13 of 27 brain regions studied. In general, the brain areas with the highest basal metabolic rates showed the greatest percentage of decrease in glucose utilization. The concept that radiation suppresses glucose utilization before any morphological change takes place in the cell structures was the basis of this study. Metabolic alterations after irradiation may explain the syndrome of early delayed deterioration observed in humans after whole-brain radiotherapy. These studies have applications to observations made with the [18F]-fluorodeoxyglucose method in conjunction with positron emission tomographic scans in patients receiving radiation therapy for intracranial malignancies. The data reported here also have potential clinical implications for the evaluation of a risk/benefit ratio for radiotherapy in patients with benign neurosurgical diseases or children undergoing prophylactic treatment of the central nervous system.