Exoscopic Microsurgery: A Change of Paradigm in Brain Tumor Surgery? Comparison with Standard Operative Microscope.

BACKGROUND: The exoscope is a high-definition telescope recently introduced in neurosurgery. In the past few years, several reports have described the advantages and disadvantages of such technology. No studies have compared results of surgery with standard microscope and exoscope in patients with glioblastoma multiforme (GBM). METHODS: Our retrospective study encompassed 177 patients operated on for GBM (WHO 2021) between February 2017 and August 2022. A total of 144 patients were operated on with a microscope only and the others with a 3D4K exoscope only. All clinical and radiological data were collected. Progression-free survival (PFS) and overall survival (OS) have been estimated in the two groups and compared by the Cox model adjusting for potential confounders (e.g., sex, age, Karnofsky performance status, gross total resection, MGMT methylated promoter, and operator's experience). RESULTS: IDH was mutated in 9 (5.2%) patients and MGMT was methylated in 76 (44.4%). Overall, 122 patients received a gross total resection, 14 patients received a subtotal resection, and 41 patients received a partial resection. During follow-up, 139 (73.5%) patients experienced tumor recurrence and 18.7% of them received a second surgery. After truncation to 12 months, the median PFS for patients operated on with the microscope was 8.82 months, while for patients operated on with the exoscope it was >12 months. Instead, the OS was comparable in the two groups. The multivariable Cox model showed that the use of microscope compared to the exoscope was associated with lower progression-free survival (hazard ratio = 3.55, 95%CI = 1.66-7.56, p = 0.001). CONCLUSIONS: The exoscope has proven efficacy in terms of surgical resection, which was not different to that of the microscope. Furthermore, patients operated on with the exoscope had a longer PFS. A comparable OS was observed between microscope and exoscope, but further prospective studies with longer follow-up are needed.

Perilesional resection technique of glioblastoma: intraoperative ultrasound and histological findings of the resection borders in a single center experience.

INTRODUCTION: The surgical goal in glioblastoma treatment is the maximal safe resection of the tumor. Currently the lack of consensus on surgical technique opens different approaches. This study describes the "perilesional technique" and its outcomes in terms of the extent of resection, progression free survival and overall survival. METHODS: Patients included (n = 40) received a diagnosis of glioblastoma and underwent surgery using the perilesional dissection technique at "San Gerardo Hospital"between 2018 and 2021. The tumor core was progressively isolated using a circumferential movement, healthy brain margins were protected with Cottonoid patties in a "shingles on the roof" fashion, then the tumorwas removed en bloc. Intraoperative ultrasound (iOUS) was used and at least 1 bioptic sample of "healthy" margin of the resection was collected and analyzed. The extent of resection was quantified. Extent of surgical resection (EOR) and progression free survival (PFS)were safety endpoints of the procedure. RESULTS: Thirty-four patients (85%) received a gross total resection(GTR) while 3 (7.5%) patients received a sub-total resection (STR), and 3 (7.5%) a partial resection (PR). The mean post-operative residual volume was 1.44 cm3 (range 0-15.9 cm3).During surgery, a total of 76 margins were collected: 51 (67.1%) were tumor free, 25 (32.9%) were infiltrated. The median PFS was 13.4 months, 15.3 in the GTR group and 9.6 months in the STR-PR group. CONCLUSIONS: Perilesional resection is an efficient technique which aims to bring the surgeon to a safe environment, carefully reaching the "healthy" brain before removing the tumoren bloc. This technique can achieve excellent tumor margins, extent of resection, and preservation of apatient's functions.

Atypical parkinsonism and intrathecal anti-glutamic acid decarboxylase antibodies - an unusual association: a case report.

BACKGROUND: Immunological causes of parkinsonism are very rare and usually characterized by early presentation, poor response to levodopa, and additional clinical features. CASE PRESENTATION: We describe a 58-year-old white man who presented with a 1-year history of gait disturbance with disequilibrium leading to falls. We report an association between parkinsonism and presence of anti-glutamic acid decarboxylase antibodies in his cerebrospinal fluid, discussing clinical presentation and follow-up. CONCLUSIONS: Besides the possibility of a casual association, this case allows us to hypothesize an alternative pathophysiological mechanism of parkinsonism implying interference with glutamic acid decarboxylase and gamma-aminobutyric acid functions, eventually resulting in basal ganglia circuit dysregulation.

Irisin and BDNF serum levels and behavioral disturbances in Alzheimer's disease.

Behavioral dysfunctions (BPSD) represent the most important problem in Alzheimer's dementia (AD) management. We assessed the serum levels of two myokines in AD patients, preliminary investigating, as secondary aim, their role as potential biomarkers for agitation/aggression (AA) and aberrant motor behavior (AMB): irisin, since it is able to modify the motor pattern, and BDNF, since it was transcribed following irisin stimulation. Forty AD patients were recruited and characterized according to the expressed neuropsychiatric syndrome. Myokines were measured by ELISA. Irisin serum levels were slightly elevated in AA+ patients (+ 10.0%; p < 0.05) and correlated with the duration of AA (r = 0.74, p < 0.03). BDNF failed to show such differences. We propose that these selected myokines are not useful as surrogate markers for agitation in AD, but might represent interesting secondary outcomes when testing drugs for those BPSD implying elevated motor activity.

Rotenone down-regulates HSPA8/hsc70 chaperone protein in vitro: A new possible toxic mechanism contributing to Parkinson's disease.

HSPA8/hsc70 (70-kDa heat shock cognate) chaperone protein exerts multiple protective roles. Beside its ability to confer to the cells a generic resistance against several metabolic stresses, it is also involved in at least two critical processes whose activity is essential in preventing Parkinson's disease (PD) pathology. Actually, hsc70 protein acts as the main carrier of chaperone-mediated autophagy (CMA), a selective catabolic pathway for alpha-synuclein, the main pathogenic protein that accumulates in degenerating dopaminergic neurons in PD. Furthermore, hsc70 efficiently fragments alpha-synuclein fibrils in vitro and promotes depolymerization into non-toxic alpha-synuclein monomers. Considering that the mitochondrial complex I inhibitor rotenone, used to generate PD animal models, induces alpha-synuclein aggregation, this study was designed in order to verify whether rotenone exposure leads to hsc70 alteration possibly contributing to alpha-synuclein aggregation. To this aim, human SH-SY5Y neuroblastoma cells were treated with rotenone and hsc70 mRNA and protein expression were assessed; the effect of rotenone on hsc70 was compared with that exerted by hydrogen peroxide, a generic oxidative stress donor with no inhibitory activity on mitochondrial complex I. Furthermore, the effect of rotenone on hsc70 was verified in primary mouse cortical neurons. The possible contribution of macroautophagy to rotenone-induced hsc70 modulation was explored and the influence of hsc70 gene silencing on neurotoxicity was assessed. We demonstrated that rotenone, but not hydrogen peroxide, induced a significant reduction of hsc70 mRNA and protein expression. We also observed that the toxic effect of rotenone on alpha-synuclein levels was amplified when macroautophagy was inhibited, although rotenone-induced hsc70 reduction was independent from macroautophagy. Finally, we demonstrated that hsc70 gene silencing up-regulated alpha-synuclein mRNA and protein levels without affecting cell viability and without altering rotenone- and hydrogen peroxide-induced cytotoxicity. These findings demonstrate the existence of a novel mechanism of rotenone toxicity mediated by hsc70 and indicate that dysfunction of both CMA and macroautophagy can synergistically exacerbate alpha-synuclein toxicity, suggesting that hsc70 up-regulation may represent a valuable therapeutic strategy for PD.

Brain targets: can you believe your own eyes?

The unquestionable advantages provided by modern neuroimaging techniques have recently led some to question the duty of the neurologist, traditionally struggling first and foremost to establish the semeiotic localization of brain lesions and only then to interpret them. The present brief report of six clinical patients who came recently to our attention aims to emphasize that the interpretation of neuroimaging results always requires integration with anamnestic, clinical and laboratory data, together with knowledge of nosography and the literature. The solutions of the reported cases always originated from close interaction between the neurologist and the neuroradiologist, based on the initial diagnostic uncertainty linked to the finding of isolated or multiple brain target or ring lesions, too often considered paradigmatic examples of the pathognomonic role of neuroimaging.

Reduced expression of the chaperone-mediated autophagy carrier hsc70 protein in lymphomonocytes of patients with Parkinson's disease.

Chaperone-mediated autophagy (CMA) impairment is recognized to play a pathogenetic role in Parkinson's disease (PD). A reduced expression of lysosomal-associated membrane protein (lamp) 2A and heat shock cognate (hsc) 70 protein, the two key regulators of CMA, has been reported in brains of PD patients. To verify the existence of a possible systemic CMA dysfunction in PD, in this study the expression of hsc70 and lamp2A was assessed in peripheral blood mononuclear cells (PBMC) of patients with sporadic PD and compared to healthy subjects. The expression of myocyte enhancer factor 2D (MEF2D), a transcriptional factor implicated in neuronal survival and specific substrate of CMA, was also evaluated. Protein and gene expression was assessed by Western blot and real-time PCR, respectively, in PBMC obtained from 53 sporadic PD patients and 53 healthy subjects. A significant reduction of hsc70 levels was observed in PBMC of PD patients, both under basal conditions and after autophagy induction obtained with serum deprivation. No difference emerged in lamp2A and MEF2D expression between patients and controls. No influence of the clinical characteristics of patients emerged on hsc70, lamp2A and MEF2D expression. These results, despite being not suggestive of the existence of a CMA impairment in PBMC of PD patients, identify a systemic hsc70 reduction in PD patients. Further studies on specific mechanisms and biological significance of such alteration are needed to corroborate this finding that could lead to the identification of a new trait biomarker for PD.

Rotenone upregulates alpha-synuclein and myocyte enhancer factor 2D independently from lysosomal degradation inhibition.

Dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson's disease (PD). Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of their de novo synthesis rather than through a reduction of their CMA-mediated degradation. Moreover, increased MEF2D transcription resulted in higher nuclear protein levels that exert a protective role against mitochondrial dysfunction and oxidative stress. These results were compared with those obtained after lysosome inhibition with ammonium chloride. As expected, this toxin induced the cytosolic accumulation of both alpha-synuclein and MEF2D proteins, as the result of the inhibition of their lysosome-mediated degradation, while, differently from rotenone, ammonium chloride decreased MEF2D nuclear levels through the downregulation of its transcription, thus reducing its protective function. These results highlight that rotenone affects alpha-synuclein and MEF2D protein levels through a mechanism independent from lysosomal degradation inhibition.

A panel of macroautophagy markers in lymphomonocytes of patients with amyotrophic lateral sclerosis.

A potential role for macroautophagy dysfunction in the pathogenesis of amyotrophic lateral sclerosis (ALS) was hypothesized after the demonstration that selected markers are up-regulated in post mortem samples obtained from both patients and animal models of disease. We hypothesized that a putative dysfunction of this catabolic pathway could be operative also in peripheral blood mononuclear cells (PBMC) obtained from ALS patients, since these cells represent an accessible model for studying molecular pathogenesis events in neuropsychiatric disorders. Beclin-1 and LC3II immunoreactivity were assessed in PBMC from 15 ALS patients and 15 controls by Western blot analysis. The expression of Atg12 mRNA was also assessed by real-time PCR. No significant difference was observed for all these parameters between patients and controls, although PBMC displayed a clear macroautophagy induction following exposure to rapamycin and lithium. Finally, we excluded a putative interference of riluzole demonstrating that LC3II immunoreactivity did not change in riluzole-treated SH-SY5Y neuroblastoma cells. In conclusion, the results of our pilot study do not support the idea of a systemic macroautophagic dysfunction in ALS, although they confirm that PBMC are a suitable peripheral marker for monitoring the effects of drugs interfering with this catabolic pathway.