Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.

Bridging integrator 1 (BIN1) is the second most prevalent genetic risk factor identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease. BIN1 encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. In vitro evidence suggests that BIN1 can directly bind to tau in the cytosol. In addition, BIN1's function limits extracellular tau seed uptake by endocytosis and subsequent propagation as well as influences tau release through exosomes. However, the in vivo roles of BIN1 in tau pathogenesis and tauopathy-mediated neurodegeneration remain uncharacterized. We generated conditional knockout mice with a selective loss of Bin1 expression in the forebrain excitatory neurons and oligodendrocytes in P301S human tau transgenic background (line PS19). PS19 mice develop age-dependent tau neuropathology and motor deficits and are commonly used to study Alzheimer's disease tau pathophysiology. The severity of motor deficits and neuropathology was compared between experimental and control mice that differ with respect to forebrain BIN1 expression. BIN1's involvement in tau pathology and neuroinflammation was quantified by biochemical methods and immunostaining. Transcriptome changes were profiled by RNA-sequencing analysis to gain molecular insights. The loss of forebrain BIN1 expression in PS19 mice exacerbated tau pathology in the somatosensory cortex, thalamus, spinal cord and sciatic nerve, accelerated disease progression and caused early death. Intriguingly, the loss of BIN1 also mitigated tau neuropathology in select regions, including the hippocampus, entorhinal/piriform cortex, and amygdala, thus attenuating hippocampal synapse loss, neuronal death, neuroinflammation and brain atrophy. At the molecular level, the loss of forebrain BIN1 elicited complex neuronal and non-neuronal transcriptomic changes, including altered neuroinflammatory gene expression, concomitant with an impaired microglial transition towards the disease-associated microglial phenotype. These results provide crucial new information on in vivo BIN1 function in the context of tau pathogenesis. We conclude that forebrain neuronal BIN1 expression promotes hippocampal tau pathogenesis and neuroinflammation. Our findings highlight an exciting region specificity in neuronal BIN1 regulation of tau pathogenesis and reveal cell-autonomous and non-cell-autonomous mechanisms involved in BIN1 modulation of tau neuropathology.

BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia.

BACKGROUND: The BIN1 locus contains the second-most significant genetic risk factor for late-onset Alzheimer's disease. BIN1 undergoes alternate splicing to generate tissue- and cell-type-specific BIN1 isoforms, which regulate membrane dynamics in a range of crucial cellular processes. Whilst the expression of BIN1 in the brain has been characterized in neurons and oligodendrocytes in detail, information regarding microglial BIN1 expression is mainly limited to large-scale transcriptomic and proteomic data. Notably, BIN1 protein expression and its functional roles in microglia, a cell type most relevant to Alzheimer's disease, have not been examined in depth. METHODS: Microglial BIN1 expression was analyzed by immunostaining mouse and human brain, as well as by immunoblot and RT-PCR assays of isolated microglia or human iPSC-derived microglial cells. Bin1 expression was ablated by siRNA knockdown in primary microglial cultures in vitro and Cre-lox mediated conditional deletion in adult mouse brain microglia in vivo. Regulation of neuroinflammatory microglial signatures by BIN1 in vitro and in vivo was characterized using NanoString gene panels and flow cytometry methods. The transcriptome data was explored by in silico pathway analysis and validated by complementary molecular approaches. RESULTS: Here, we characterized microglial BIN1 expression in vitro and in vivo and ascertained microglia expressed BIN1 isoforms. By silencing Bin1 expression in primary microglial cultures, we demonstrate that BIN1 regulates the activation of proinflammatory and disease-associated responses in microglia as measured by gene expression and cytokine production. Our transcriptomic profiling revealed key homeostatic and lipopolysaccharide (LPS)-induced inflammatory response pathways, as well as transcription factors PU.1 and IRF1 that are regulated by BIN1. Microglia-specific Bin1 conditional knockout in vivo revealed novel roles of BIN1 in regulating the expression of disease-associated genes while counteracting CX3CR1 signaling. The consensus from in vitro and in vivo findings showed that loss of Bin1 impaired the ability of microglia to mount type 1 interferon responses to proinflammatory challenge, particularly the upregulation of a critical type 1 immune response gene, Ifitm3. CONCLUSIONS: Our convergent findings provide novel insights into microglial BIN1 function and demonstrate an essential role of microglial BIN1 in regulating brain inflammatory response and microglial phenotypic changes. Moreover, for the first time, our study shows a regulatory relationship between Bin1 and Ifitm3, two Alzheimer's disease-related genes in microglia. The requirement for BIN1 to regulate Ifitm3 upregulation during inflammation has important implications for inflammatory responses during the pathogenesis and progression of many neurodegenerative diseases.

High-strength and fibrous capsule-resistant zwitterionic elastomers.

The high mechanical strength and long-term resistance to the fibrous capsule formation are two major challenges for implantable materials. Unfortunately, these two distinct properties do not come together and instead compromise each other. Here, we report a unique class of materials by integrating two weak zwitterionic hydrogels into an elastomer-like high-strength pure zwitterionic hydrogel via a "swelling" and "locking" mechanism. These zwitterionic-elastomeric-networked (ZEN) hydrogels are further shown to efficaciously resist the fibrous capsule formation upon implantation in mice for up to 1 year. Such materials with both high mechanical properties and long-term fibrous capsule resistance have never been achieved before. This work not only demonstrates a class of durable and fibrous capsule-resistant materials but also provides design principles for zwitterionic elastomeric hydrogels.

Identifying factors influencing mortality in patients aged over 65 following an acute type II odontoid process fracture. A retrospective cohort study.

OBJECTIVE: Compare short-term mortality rates following operative and nonoperative management of geriatric patients following an acute type II odontoid process fracture. METHODS: One hundred forty-one patients with a type II odontoid fracture were identified from a single centre between 2002 and 2018. Patient demographics, details of injury and management, plus mortality data were collected. The incidence of mortality at 3 and 12 months was calculated, and a multivariate model built which included the treatment modality variable and allowed adjustment for six individual confounders. RESULTS: Of the 141 patients with a type II odontoid process fracture, 39 were managed operatively, while 102 were managed nonoperatively. Relative to the nonoperative group, the operative group was younger (79.0 ± 7.0 vs. 83.7 ± 7.6), more likely to have odontoid angulation > 15° (74.4% vs. 43.1%, p < 0.01), and a greater proportion having fracture displacement > 2 mm (74.4% vs. 31.4%, p < 0.01). Both groups were comparable for gender, comorbidities, and associated injuries. On univariate analysis of treatment modality, the odds ratio of 3-month mortality with nonoperative management was 2.55 (95% CI: 0.82-7.92; p = 0.08), whilst at 12-months it was 3.12 (95% CI: 1.11-8.69; p = 0.02). On multivariate analysis of 12-month mortality, however, treatment modality was not found to be significant. This multivariate analysis suggested that increasing age, male gender, and injury severity were significant predictors of 12-month mortality. CONCLUSION: In contrast to the findings of a number of previous studies, operative management may not influence survival at 3- and 12-months.

Modified C1 lateral mass screw insertion using a threaded K-wire. A technical note.

Instrumented fixation of the C1-C2 motion segment is a standard surgical technique to stabilise that spinal segment. Instability at C1-C2 can arise from a number of conditions. Fixation of the C1 lateral mass usually involves dissection and exposure of the C2 nerve root and the posterior wall of the C2 lateral mass which can result in significant bleeding from the venous plexus. Whilst image guidance is increasing in accessibility, there are few public hospitals in Australia that have access to this technology. The authors describe their technique for insertion of a C1 lateral mass screw over a threaded K-wire to avoid extensive dissection of the C2 nerve root, reducing the risk of significant haemorrhage from the epidural venous plexus during the procedure. A retrospective analysis was undertaken on 18 consecutive patients who underwent C1-C2 instrumented fixation using this technique. Indications for C1-C2 instrumented fixation included traumatic injury (10 patients), failure of non-operative management of odontoid fractures (5 patients), pathological fractures of C2 (2 patients) and inflammatory conditions (1 patient). All patients underwent successful C1-C2 stabilisation using this technique. Blood loss did not exceed 400mls in any patient. There were no vertebral artery injuries and no patient experienced a neurological deterioration. The authors propose that their technique for insertion of a C1 lateral mass screw over a threaded K-wire is safe and effective with a low risk of neurological or vertebral artery injury. The technique may be considered as a slight modification of the Harm's procedure to reduce disturbance of the adjacent venous plexus and thereby reduction in intraoperative bleeding and operative time.

Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation.

BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using conditional knockout (cKO) models. Loss of neuronal Bin1 expression results in the select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses reveals a deficit in presynaptic release probability and slower depletion of neurotransmitters during repetitive stimulation, suggesting altered vesicle dynamics in Bin1 cKO mice. Super-resolution and immunoelectron microscopy localizes BIN1 to presynaptic sites in excitatory synapses. Bin1 cKO significantly reduces synapse density and alters presynaptic active zone protein cluster formation. Finally, 3D electron microscopy reconstruction analysis uncovers a significant increase in docked and reserve pools of synaptic vesicles at hippocampal synapses in Bin1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing significant insights into the fundamental function of BIN1 in synaptic physiology relevant to Alzheimer disease.

Outcomes for Vertebrectomy for Malignancy and Correlation to the Spine Instability Neoplastic Score (SINS): a 10-Year Single-Center Perspective.

OBJECTIVE: The clinical prognostic value of the Spinal Instability Neoplastic Score (SINS), in the context of vertebrectomy for neoplasia, has not yet been established. This retrospective study of 134 patients aims to evaluate the efficacy of the SINS to predict outcomes and survival after vertebrectomy for malignancy. METHODS: The patients were classified into 2 groups: indeterminate stability (SINS 7-12) and unstable (SINS 13-18). Outcomes assessed included survival days after procedure, neurological function (modified Frankel grade), operative time, blood loss, complications, construct failure, and length of inpatient stay. RESULTS: The indeterminate group included 68 patients, whereas the unstable group included 66 patients. No patients were classified as stable (SINS 0-6). The median survival was 225 days (interquartile range, 81-522 days). There was a statistically significant difference (P < 0.001) in survival days after vertebrectomy between the indeterminate group (435 days) and the unstable group (126 days). The majority of patients (119) had a favourable Frankel grade after procedure with no significant difference between SINS groups (P = 0.534). There were no differences in the operative time (234 vs. 210; P = 0.130), inpatient hospital length of stay (10 days vs. 11 days; P = 0.152), complications, or need for intensive care admission (intensive care unit) between the 2 cohorts. There was a statistically significant difference (P = 0.006) for intraoperative blood loss between the indeterminate group (1400 mL) and the unstable group (850 mL). CONCLUSIONS: This study demonstrates a statistically significant increased survival in the indeterminate cohort. These results demonstrate the potential ability of the SINS to act as a clinical prognostic tool with regard to survival time.

Vertebrectomy in metastatic spinal tumours: A 10 year, single-centre review of outcomes and survival.

Metastatic disease to the vertebral column can cause spinal instability, neurological deterioration and pain. The present study was designed to provide insight into the cohort undergoing vertebrectomy for metastatic disease to the spinal column, assessing the associated morbidity, functional outcomes and survival. A retrospective review of 141 consecutive vertebrectomies for metastatic disease was undertaken. The procedures were performed between 2006 and 2016 at a single institution. Medical records were reviewed and data was obtained regarding primary malignancy, presenting symptoms, pre-operative chemotherapy or radiotherapy, Spinal Instability Neoplastic Score, neurological function, operative approach and duration, blood loss, transfusion requirement, complications, survival, delayed neurological deterioration and construct failure. Long-term follow-up data was available for 123 patients. Forty-two patients were alive at the time of review with a mean survival of 464 days. Post-operative neurological function was preserved or improved in 96.5% of patients. Five patients suffered a neurological deterioration post-operatively. The major complication rate was 19.8% with the most frequent complication being wound infection or dehiscence requiring revision. There were four inpatient deaths. Mean operative time was 240 min. Mean blood loss was 1490 mls. When assessing results by age, no significant difference with respect to complications, neurological outcomes or survival was demonstrated in patients over age 65. There was a significant reduction in survival and higher complication rates in patients who were non-ambulatory following vertebrectomy. Vertebrectomy is a safe and effective means of providing circumferential neural decompression and stabilization with an acceptable complication rate in patients with vertebral metastases, irrespective of age.

Favourable Outcome in a 33-Year-Old Female with Acute Haemorrhagic Leukoencephalitis.

BACKGROUND: Acute haemorrhagic leukoencephalitis (AHLE) is a rare and rapidly fatal disease of unknown aetiology. There is a paucity of literature on the presentation and management of this rare disease. CASE DESCRIPTION: We report the case of a 33-year-old female presenting with headache and left-sided apraxia. Imaging revealed a right-sided white matter lesion with extensive cytotoxic oedema. Pathology was suggestive of AHLE. She underwent an open excisional biopsy and was treated with high-dose corticosteroids. Three months since symptom onset she remains clinically well with resolving apraxia and radiological appearance. CONCLUSION: This case may represent a milder spectrum of AHLE, which responded favourably to corticosteroids.

Fluorescence in a cryptococcoma following administration of 5-aminolevulinic acid hydrochloride (Gliolan).

A 54-year-old man presented with two episodes of dysarthria and left facial droop. Both episodes resolved by the time of examination. MRI of the brain revealed a right frontotemporal, heterogeneously enhancing mass with surrounding vasogenic oedema, suggestive of a high-grade primary brain neoplasm. The patient was administered preoperative 5-aminolevulinic acid hydrochloride (Gliolan), and fluorescence-guided resection of the lesion was undertaken. Cryptococcus gattii infection was diagnosed from the specimen and the patient was given appropriate antifungal treatment. This is the first reported case of Gliolan-mediated fluorescence in a fungal abscess and highlights one of the potential pitfalls in fluorescence-guided surgery.

An fMRI Study of the Impact of Block Building and Board Games on Spatial Ability.

Previous studies have found that block play, board games, and puzzles result in better spatial ability. This study focused on examining the differential impact of structured block play and board games on spatial processing. Two groups of 8-year-old children were studied. One group participated in a five session block play training paradigm and the second group had a similar training protocol but played a word/spelling board game. A mental rotation task was assessed before and after training. The mental rotation task was performed during fMRI to observe the neural changes associated with the two play protocols. Only the block play group showed effects of training for both behavioral measures and fMRI measured brain activation. Behaviorally, the block play group showed improvements in both reaction time and accuracy. Additionally, the block play group showed increased involvement of regions that have been linked to spatial working memory and spatial processing after training. The board game group showed non-significant improvements in mental rotation performance, likely related to practice effects, and no training related brain activation differences. While the current study is preliminary, it does suggest that different "spatial" play activities have differential impacts on spatial processing with structured block play but not board games showing a significant impact on mental rotation performance.

Cervical spine immobilization following blunt trauma: a systematic review of recent literature and proposed treatment algorithm.

BACKGROUND: Management of the cervical spine following blunt trauma is commonplace. In 2013, the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) published practice guidelines drawn from evidence dating to 2011. Since then, further publications have emerged that are reviewed, and a simple management algorithm produced to assist practitioners in Australian trauma centres. These publications attempt to shed light on two controversial scenarios, those being the management of symptomatic patients with negative computed tomography (CT) and management of the obtunded patient. METHODS: The search strategy mirrored that of the AANS/CNS guidelines. A search of the National Library of Medicine (PubMed) database for manuscripts published between January 2011 and October 2014 was conducted. One reviewer extracted data from studies assessing the performance of various imaging modalities in identifying traumatic cervical spine injuries. In clinical scenarios where little evidence has emerged since the AANS/CNS guidelines, key manuscripts published prior to 2011 were identified from bibliographies. RESULTS: Awake, asymptomatic patients may be 'cleared' without further imaging. Awake, symptomatic patients without pathology on CT and without neurological deficit can safely be 'cleared' without magnetic resonance imaging. There is no longer a role for flexion-extension films. In the obtunded patient, findings remain conflicting. CONCLUSION: Several of these findings represent a departure from previous practices, including clearance of patients with non-neurological symptoms on the basis of CT and the exclusion of flexion-extension film in detecting injury. Management of the obtunded patient remains controversial.

Reliability of quantitative magnetic resonance imaging methods in the assessment of spinal canal stenosis and cord compression in cervical myelopathy.

STUDY DESIGN: Prospective, blinded reliability study of quantitative magnetic resonance imaging (MRI) measures in patients with cervical myelopathy. OBJECTIVE: To assess the intra- and interobserver reliability of commonly used quantitative MRI measures such as transverse area (TA) of spinal cord, compression ratio (CR), maximum canal compromise (MCC), and maximum spinal cord compression (MSCC). SUMMARY OF BACKGROUND DATA: There is no consensus on an optimal quantitative MRI method(s) in assessing canal stenosis and cord compression. METHODS: Seven surgeons performed measurements on 17 digital MR images, on 4 separate occasions. The degree of stenosis was evaluated by measuring TA and CR on axial T2, MCC, and MSCC on midsagittal T1- and T2-weighted MRI sequences, respectively. Statistical analyses included repeated-measures analysis of variance and intraclass correlation coefficients (ICCs). RESULTS: The mean ± SD for intraobserver ICC was 0.88 ± 0.1 for MCC, 0.76 ± 0.08 for MSCC, 0.92 ± 0.07 for TA, and 0.82 ± 0.13 for CR. In addition, the interobserver ICC was 0.75 ± 0.04 for MCC, 0.79 ± 0.09 for MSCC, 0.80 ± 0.05 for CR, and 0.86 ± 0.03 for TA. Higher degree of canal compromise (MCC) was associated with lower modified version of Japanese Orthopaedic Association Scale score (P = 0.05). Also, a strong association was found between MSCC and lower modified version of Japanese Orthopaedic Association Scale score, greater number of steps, and longer walking time (P < 0.05). CONCLUSION: All 4 measurement techniques demonstrated a good to moderately high degree of intra- and interobserver reliability. Highest reliability was noted in the assessment of T2-weighted sequences and axial MRI. Our results show that the measurements of MCC, MSCC, and CR are sufficiently reliable and correlate well with clinical severity of cervical myelopathy.

Does postsurgical cervical deformity affect the risk of cervical adjacent segment pathology? A systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To assess whether the presence or magnitude of postsurgical malalignment in the coronal (scoliosis) or sagittal plane (kyphosis/spondylolisthesis) affects the risk of cervical adjacent segment pathology (ASP). SUMMARY OF BACKGROUND DATA: ASP occurs in selected patients who have undergone surgical treatment for cervical spondylosis. The reasons are multifactorial; however, postsurgical alignment may play a key role. To elucidate this issue, a systematic review of the literature was undertaken. METHODS: A systematic search in PubMed was conducted for literature published in English language through February 15, 2012. Studies in adults, designed to evaluate postsurgical sagittal or coronal malalignment as risk factors for radiographical or clinical ASP, were sought. Studies of pediatric or oncological patients were excluded. Case reports, case series, and patient populations of less than 10 patients were also excluded. Unadjusted risk ratios (RRs) and 95% confidence intervals were calculated to evaluate the association between alignment and the risk for developing ASP. RESULTS: The search yielded 338 citations. Of that, 311 were excluded at the title and abstract level. Of the 27 selected for full-text review, 5 poor-quality retrospective studies met the inclusion criteria and described sagittal imbalance measures as risk factors for radiological ASP after anterior surgery. No studies examined ASP after posterior cervical surgery. Three studies provided data from which unadjusted RRs and 95% confidence intervals could be calculated. These studies showed an increased risk of ASP associated with malalignment (RR, 2.24 [95% confidence interval, 1.40-3.56]; RR, 2.40 [1.33, 4.33]; RR, 1.32 [0.96, 1.81]). No study evaluating coronal imbalance as a risk factor for cervical ASP was found and none reported on clinical ASP. CONCLUSION: There is low-grade evidence from 3 published studies that postsurgical sagittal imbalance may increase the risk for cervical radiological ASP. CONSENSUS STATEMENT: An attempt should be made to maintain or restore cervical lordosis in surgical intervention for cervical disorders. Strength of Statement: Weak.

Enzymatic digestion in stomachless fishes: how a simple gut accommodates both herbivory and carnivory.

The lack of a stomach is not uncommon amongst teleost fishes, yet our understanding of this reductive specialisation is lacking. The absence of a stomach does not restrict trophic preference, resulting in fishes with very similar alimentary morphology capable of digesting differing diets. We examined the digestive biochemistry of four beloniform fishes: two herbivorous halfbeaks (Hemiramphidae) and two carnivorous needlefish (Belonidae) to determine how these fishes digest their respective diets with their simple, short gut. We found that although the halfbeaks showed significantly greater α-amylase activity than that of the needlefish (P < 0.01), trypsin, lipase, aminopeptidase and maltase activity were not substantially different between the two families. We also found that habitat (freshwater vs. marine) appears to play a significant role in digestive capability, as the two freshwater taxa and the two marine taxa were significantly different (ANOSIM; dietary Gobal R = 0.544, P = 0.001, habitat Global R = 0.437, P = 0.001), despite their phyletic and dietary similarities. Our findings offer partial support for the adaptive modulation hypothesis, support the Plug-Flow Reactor model of digestion in herbivorous halfbeaks and also support the compartmental model of digestion but suggest that another model is required to describe stomachless carnivorous needlefish.

Endoscopic transnasal decompression for management of basilar invagination in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a disorder of bone development caused by a genetic dysfunction of collagen synthesis. Basilar invagination (BI) is an uncommon but serious complication of OI. Brainstem decompression in OI is undertaken in certain circumstances. Transoral-transpalatopharyngeal ventral decompression with posterior occipitocervical fusion has become the treatment of choice when required. This technical note outlines a novel endoscopic transnasal approach for ventral decompression. The literature is reviewed and a strategy for the management of BI in patients with OI is outlined.

A rare presentation of pigmented villonodular synovitis.

Tenosynovial giant cell tumours are of two types, localised and diffuse. The diffuse type is also known as pigmented villonodular synovitis (PVNS). There have been 42 previously reported cases of PVNS in the axial skeleton, seven of which were reported in the thoracic spine. A young patient found to have thoracic PVNS and who presented with progressive lower limb weakness and parasthesiae over 3 weeks is reported. Computed tomography and magnetic resonance imaging demonstrated a posterior lesion at T6/7 with local bone invasion. The patient underwent complete resection of the tumour and has had an unremarkable postoperative convalescence with resolution of his signs and symptoms. Total surgical resection is the treatment of choice for this condition and close postoperative follow-up with serial imaging is important to monitor for local recurrence.