Search

Abstract Background Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. Methods In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. Results Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. Conclusion Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD. Graphical Abstract

Superior cerebellar artery (SCA) aneurysms are rare, especially for those arising from the distal portion of the SCA. In this study, we presented a case of a ruptured aneurysm arising from cerebellomesencephalic segment of the SCA. A woman with severe headache and neck stiffness had a ruptured aneurysm arising from cerebellomesencephalic segment of the left SCA. Treated successfully with left-sided paramedian supracerebellar infratentorial (SCIT) approach for clipping the aneurysm with a sitting position, discharged after 14 days without neurological deficit. SCA aneurysms can be managed by endovascular coiling or microsurgical clipping. Although both modalities pose risks of damaging the brainstem perforators, the incidence of the SCIT approach is low since it is exposure from laterally to medially and from distal to proximal along the course of SCA. In our viewpoint, the paramedian SCIT approach is a safe and effective treatment for clipping aneurysms arising from the distal portion of the SCA.

Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) has cytoprotective effects on various injuries, including cerebral ischemia, and it can promote recovery even when delivered intracranially several days after ischemic stroke. In the uninjured rodent brain, MANF protein is expressed almost exclusively in neurons, but post-ischemic MANF expression has not been characterized. We aimed to investigate how endogenous cerebral MANF protein expression evolves in infarcted human brains and rodent ischemic stroke models. During infarct progression, the cerebral MANF expression pattern both in human and rat brains shifted drastically from neurons to expression in inflammatory cells. Intense MANF immunoreactivity took place in phagocytic microglia/macrophages in the ischemic territory, peaking at two weeks post-stroke in human and one-week post-stroke in rat ischemic cortex. Using double immunofluorescence and mice lacking MANF gene and protein from neuronal stem cells, neurons, astrocytes, and oligodendrocytes, we verified that MANF expression was induced in microglia/macrophage cells in the ischemic hemisphere. Embarking on the drastic expression transition towards inflammatory cells and the impact of blood-borne inflammation in stroke, we hypothesized that exogenously delivered MANF protein can modulate tissue recovery processes. In an attempt to enhance recovery, we designed a set of proof-of-concept studies using systemic delivery of recombinant MANF in a rat model of cortical ischemic stroke. Intranasal recombinant MANF treatment decreased infarct volume and reduced the severity of neurological deficits. Intravenous recombinant MANF treatment decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokine IL-10 in the infarcted cortex one-day post-stroke. In conclusion, MANF protein expression is induced in activated microglia/macrophage cells in infarcted human and rodent brains, and this could implicate MANF’s involvement in the regulation of post-stroke inflammation in patients and experimental animals. Moreover, systemic delivery of recombinant MANF shows promising immunomodulatory effects and therapeutic potential in experimental ischemic stroke.

Abstract During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH.

The natural course of pineal germ cell tumors (GCTs), particularly their post-operative progression, is not well understood. We report a rare case of pineal region GCT showing rapid enlargement within 2 weeks following surgical resection. A young adult male presented with progressive headache and diplopia for several weeks. Although elevation of β-human chorionic gonadotropin (β-HCG) and α-fetoprotein (AFP) levels suggested that a large pineal mass lesion observed on magnetic resonance imaging (MRI) might be a β-HCG/AFP-producing tumor, whether the mass was truly a GCT remained unclear. We performed an endoscopy-assisted suboccipital infratentorial approach with removal of the tumor that was diagnosed as germinoma via histopathological investigation. During the week preceding chemotherapy, the patient’s consciousness rapidly worsened. MRI showed that the residual pineal germinoma had enlarged and even compressed the tectum and thalamus. Emergency chemotherapy and radiotherapy were prescribed, and the patient received invasive ventilation for respiratory failure. Unexpectedly, the patient recovered within a short period. Importantly, total regression of the pineal germinoma, accompanied by β-HCG and AFP levels returning to normal range, was observed 4 months after chemotherapy. These phenomena suggest that the rapid enlargement of the pineal germinoma, which might be induced by aggressive surgical cytoreduction, responds well to chemoradiotherapy.

Background: Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has shown to have smaller skin incision, decreased muscular dissection, and less retraction of the thecal sac, compared to conventional open approach. However, its effects on long term functional outcome and degenerative changes of paraspinal muscles are still obscure. Materials and Methods: We studied 81 patients treated by one team of surgeons at a single institution. In the two level spinal fusion, 18 patients underwent conventional TLIF (C TLIF) and 20 patients underwent MIS TLIF. In three level spinal fusion, 23 patients were treated with C TLIF and 20 patients were treated with MIS TLIF. Clinical outcomes included mean operative times, volume of blood loss, percentage of early ambulation, visual analog scale (VAS), and oswestry disability index (ODI) were analyzed. The change of multifidus muscle was calculated from magnetic resonance imaging (MRI) taken before and 6-month after the operation. Results: Lesser blood loss was noted in the MIS TLIF group compared to the conventional group in two- or three-level circumferential spinal fusion. Early ambulation (within 3 days after operation) was found in the MIS TLIF groups. Analysis of VAS scores at leg area showed no significant differences in improvement between each group at 18 month follow up. The postoperative ODI score was significantly less in the MIS TLIF groups than in the C TLIF groups after 6 month follow up. In three segment spinal fusion, MIS TLIF minimized multifidus muscle atrophy, when compared with C TLIF. Conclusion: MIS TLIF in three level lumbar fusion not only has a better functional recovery but also ameliorates the degenerative change of multifidus muscle.

Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF’s function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery. Next, we investigated the number and morphological characteristic of peri-infarct microglia at different time points and elucidated the mechanism of microglial response by VPA treatment. Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 min, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 min after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 h after reperfusion, and neurological symptoms were evaluated. VPA didn’t significantly reduce infarct volume but did ameliorate neurological deficit at least partially compared with vehicle. Meanwhile, VPA reduced dMCAo-induced elevation of IL-6 at 24 h post-stroke and significantly decreased the number of CD11b-positive microglia within peri-infarct cortex at 7 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions, smaller soma size and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 and 7 days, suggesting that VPA has core effects on microglial morphology. The modulation of microglia morphology caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Furthermore, qPCR analysis of CD11b-positive cells at 3 days post-stroke suggested that VPA could partially enhance M2 subset polarization of microglia in peri-infarct cortex. Analysis of VPA-induced changes to gene expressions at 3 days post-stroke implies that these alternations of the biomarkers and microglial responses are implicated in the upregulation of wound healing, collagen trimmer, and extracellular matrix genes within peri-infarct cortex. Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the morphological characteristics and transcriptional profiles of microglia and extracellular matrix remodeling, which could contribute to the improved recovery.

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.

Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV-BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.

Background/Aim: Spontaneous spinal epidural hematoma (SSEH) is a rare but serious condition, accounting for less than 1% of spinal lesions, with an incidence of 0.1 per 100,000 annually. Discovered by Jackson in 1869, around 40-50% of SSEH cases often lack a definitive cause, though risk factors, such as anticoagulant usage, vascular malformations, and hypertension are recognized. Symptoms vary from mild pain to severe neurological impairments like paraparesis, depending on the spinal cord compression level. Prompt treatment, usually involving spinal decompression and hematoma removal, is crucial, especially in cases of neurological decline. The study aims to provide comprehensive analysis of SSEH through examination of by patient cases, critical prognostic factors, and therapeutic strategies, based on demographics, clinical data, and outcomes observed at the Tri-Service General Hospital. Patients and Methods: This retrospective study, spanning 2003-2023 at the Tri-Service General Hospital, analyzed 14 patients with SSEH. It examined demographics, risk factors, clinical and radiological profiles, treatments, outcomes, and prognoses, using SPSS software (version 22.0) and adhering to the Modified Rankin Scale (mRS) and the American Spinal Injury Association (ASIA) impairment scale guidelines for data analysis. Results: In this study of 14 patients with SSEH, 93% underwent urgent surgery, including total laminectomy or open-door laminoplasty, while 7% received conservative treatment. Postsurgery, 69.2% showed favorable outcomes (mRS ≤2) in the one-year follow-up, while 30.8% had poorer results (mRS 3- 4). A significant negative correlation was noted between initial ASIA scores and one-year mRS outcomes, suggesting less initial impairment predicts better recovery. These findings indicated that a moderate positive correlation between treatment delay and one-year mRS scores. Nevertheless, factors, such as age, antiplatelet use, spinal levels with hematoma localization, and myelopathy signs observed before treatment did not demonstrate any significant effects on neurological outcomes during the one-year follow-up. Conclusion: Patients with minor initial deficits or those receiving early surgery, preferably within 12-36 h of symptom onset, exhibit better neurological recovery. Poor prognosis correlates with high International Normalized Ratio (INR) on anticoagulants, hematoma size, lumbar involvement, or severe motor issues. Rapid surgical hematoma evacuation is advised. Our study supports recovery of neurological function following surgical intervention in all cases, highlighting the potential efficacy of surgical decompression even in severe and prolonged instances of SSEH. [ABSTRACT FROM AUTHOR]

Background: There is accumulating evidence that Vitamin D deficiency contributes to the occurrence of stroke, including ischemic and hemorrhagic strokes. However, the relationship between Vitamin D levels and the risk of hemorrhage stroke was less conclusive. Aim: This prospective study is aimed for relationship between Vitamin D status and specific nonlobar hemorrhagic stroke in a Taiwanese cohort. Methods: A prospective study of 44 adult patients (32 males and 12 females; 27 aged <65 years and 17 ≥65 years) with acute nonlobar spontaneous intracerebral hemorrhage (sICH) was undertaken for 24 months (December 2017–November 2019) in a general reference teaching hospital. The serum 25‑hydroxyvitamin D (25(OH) D) level was examined within 1 day of the stroke. The associations between Vitamin D status, age, low‑density lipoprotein levels, and hemorrhagic stroke were analyzed using the Chi‑squared test for comparisons. Statistical significance was set at P < 0.05. Results: The mean serum concentration of (25(OH) D) was 20.30 ng/ml. There were 14 patients with Vitamin D insufficiency (<30 ng/ml), and 23 with Vitamin D deficiency (<20 ng/ml). There was no age dependence to the Vitamin D deficiency and insufficiency in patients with acute nonlobar sICH. We also found no significant correlation between Vitamin D deficiency and low‑density lipoprotein concentration. Conclusion: A particularly high prevalence of Vitamin D deficiency was found in Taiwanese patients with specific hemorrhagic stroke, acute nonlobar sICH, and this was independent of age or serum low‑density lipoprotein levels. [ABSTRACT FROM AUTHOR]

Background/Aim: To investigate the radiographic and clinical outcomes in patients diagnosed with multilevel lumbar spine degeneration, undergoing hybrid stabilization with an interspinous device (IPD) adjacent to spine fusion, as compared with those experiencing three-segment or twosegment transforaminal lumbar interbody fusion (TLIF) via minimally invasive surgery (MIS). Patients and Methods: Between 2015-2017, 51 consecutive patients who received three-segment TLIF, interspinous dynamic stabilization combined with two-segment TLIF (topping-off surgery), and two-segment TLIF coupled with adjacent level lumbar discectomy (two-segment TLIF+discectomy) were studied. These three operative procedures were performed by one neurosurgeon at the same hospital. Post-operative analysis of the two-year analysis was conducted by another neurosurgeon. Radiographic and clinical outcomes were compared among the three groups. Results: Duration of surgery was significantly shorter in the topping-off surgery and TLIF+discectomy compared to three-segment TLIF group. Although there was no difference in hospital stay among the three groups, visual analogue scale (VAS) and Oswestry disability index (ODI) were less in the topping-off group than in the three-segment TLIF or two-segment TLIF+discectomy groups after one week and three months follow-up, respectively. Disc high index (DHI) in adjacent segment decreased from before the operation to two years follow-up postoperatively in the two-segment TLIF+discectomy group. In contrast, DHI in the segment adjacent to spondylolisthesis increased from before the operation to last follow-up post-operatively in the threesegment TLIF group. Compared with the two-segment TLIF+discectomy group, the topping-off group showed higher foramen high index at the IPD level. While there was no difference in segment range of motion among the three groups, the topping-off group showed preserved total range of motion at a two-year follow-up, as compared with the three-segment TLIF group. Conclusion: Under strict indications, topping-off surgery is an acceptable alternative to fusion surgery for spondylolisthesis combined with adjacent disc degeneration. [ABSTRACT FROM AUTHOR]

Tumors located within the third ventricle have some potential limitations during surgical approach. Generally speaking, it is impossible to reach the third ventricle without incision of any neural structure. We report a patient with choroid glioma in the anterior part of the third ventricle, and coincident cavum septum pellucidum (CSP) in whom we could remove the tumor gross totally without damaging any neurovascular structures. The tumor expanded the space between the rostrum of the corpus callosum and the column of the fornix and lifted up the floor of CSP. The transcavum-septum-pellucidum approach anterior to foramen of Monro was chosen to remove the anterior third ventricle tumor. We propose that the tumor had likely expanded within the above-mentioned space and elevated the floor of CSP thus increasing the anteroposterior diameter of the floor providing a feasible avenue to third ventricle making it feasible to pass through the enlarged space safely. Overall, cavum septum pellucidum provided a feasible route to approach the anterior third ventricle directly. [ABSTRACT FROM AUTHOR]

Skull bone metastasis from the gastric cancer is a rare. We reported a 52-year-old male proven to have stomach cancer and who underwent subtotal gastrectomy 5 months previously. Within the past 2 weeks, he experienced headache and dizziness followed by weakness of the left lower limb. A diagnosis of right chronic subdural hematoma (SDH) was made, and a burr hole was performed for drainage of the hematoma. However, 5 days later, the patient had sudden loss of consciousness without external evidence of trauma to the head. An emergency computed tomography (CT) scan revealed a high-density lesion consistent with an acute SDH on the right side. Histologically, metastasis of gastric adenocarcinoma was detected in both the dura mater and skull. It is suggested that the SDH was caused by the rupture of vessels in the metastasis or rupture of the inner dural vessels, possibly resulting from congestion of the outer vessels.