The lateral transorbital approach to the medial sphenoid wing, anterior clinoid, middle fossa, cavernous sinus, and Meckel's cave: target-based classification, approach-related complications, and intermediate-term ocular outcomes.

OBJECTIVE: The lateral transorbital approach (LTOA) is a relatively new minimal access skull base approach suited for addressing paramedian pathology of the anterior and middle fossa. The authors define target zones for this approach and describe a series of cases with detailed measurements of visual outcomes, including those obtained with exophthalmometry. METHODS: The authors performed a retrospective analysis of a consecutive series of LTOA patients. Seven target zones were identified: 1) the orbit, 2) the lesser sphenoid wing and anterior clinoid, 3) the middle fossa, 4) the lateral wall of the cavernous sinus and Meckel's cave, 5) the infratemporal fossa, 6) the petrous apex, and 7) the anterior fossa. The authors used volumetric analyses of preoperative and postoperative MR and CT imaging data to calculate the volume of bone and tumor removed and to provide detailed ophthalmological, neurological, and cosmetic outcomes. RESULTS: Of the 20 patients in this cohort, pathology was in zone 2 (n = 10), zone 4 (n = 6), zone 3 (n = 2), zone 1 (n = 1), and zone 5 (n = 1). Pathology was meningioma (n = 10), schwannoma (n = 2), metastasis (n = 2), epidermoid (n = 1), dermoid (n = 1), encephalocele (n = 1), adenoma (n = 1), glioblastoma (n = 1), and inflammatory lesion (n = 1). The goal was gross-total resection (GTR) in 9 patients, all of whom achieved GTR. Subtotal resection (STR) was the goal in 8 patients (5 spheno-orbital meningiomas, 1 giant cavernous sinus/Meckel's cave schwannoma, 1 cavernous sinus prolactinoma, and 1 cavernous sinus dermoid), 7 of whom achieved STR and 1 of whom achieved GTR. The goal was biopsy in 2 patient and repair of encephalocele in 1. Visual acuity was stable or improved in 18 patients and worse in 2. Transient early postoperative diplopia, ptosis, eyelid swelling, and peri-orbital numbness were common. All 9 patients with preoperative diplopia improved at their last follow-up. Seven of 8 patients with preoperative exophthalmos improved after surgery (average correction of 64%). There were no cases of clinically significant (> 2 mm) postoperative enophthalmos. The most frequent postoperative complaint was peri-orbital numbness (40%). There was 1 CSF leak. Most patients were satisfied with their ocular (84%-100% of patients provided positive satisfaction-related responses) and cosmetic (75%-100%) outcomes. CONCLUSIONS: The LTOA is a safe minimal access approach to a variety of paramedian anterior skull base pathologies in several locations. Early follow-up revealed excellent resolution of exophthalmos with little risk of clinically significant enophthalmos. Transient diplopia, ptosis, and peri-orbital numbness were common but improved. Careful case selection is critical to ensure good outcome.

METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.

BACKGROUND: N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD). METHODS: We investigated the m6A modification and the expression of m6A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m6A levels on AD-related deficits both in vitro and in vivo. RESULTS: We found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m6A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m6A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aß oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aß-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aß-induced synaptic damage and cognitive impairment in vivo. CONCLUSIONS: Collectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

Mfn2 Overexpression Attenuates MPTP Neurotoxicity In Vivo.

Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson's disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP+ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death.

It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer's disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways.