Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing.

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

A neurosurgical approach to traumatic brain injury and post-traumatic hypopituitarism.

PURPOSE: Traumatic brain injury (TBI) is a common cause of mortality and major disability worldwide. The initial management often depends on the severity of the injury. Pituitary dysfunction can develop as a sequela of TBI, and can have long-term, debilitating impact on the patients. Early identification and prompt intervention of post-traumatic hypopituitarism (PTHP) is essential to prevent or minimize the adverse consequences of this condition. We hereby provide an overview of the current management of TBI from a neurosurgical standpoint. We then review the pathophysiology and risk factors of developing PTHP, as well as our recommendations for its management. METHODS: A review of current literature on TBI and PTHP, including primary research articles, reviews and clinical guidelines. RESULTS: The current neurosurgical approach to the management of TBI is presented, followed by the pathophysiology and risk factors of PTHP, as well as our recommendations for its management. CONCLUSIONS: Post-traumatic hypopitutiarism is a serious and potentially debilitating condition that is likely under-recognised and under-diagnosed. From a neurosurgical perspective, we advocate a pragmatic approach, i.e. screening those considered at high risk of developing PTHP based on clinical features and biochemical/endocrinological testings; and referring them to a specialist endocrinologist for further management as indicated.

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance.

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.

Full length talin stimulates integrin activation and axon regeneration.

Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, which bind to the intracellular tail of beta integrins. Previous studies have shown that the axon growth inhibitory molecules NogoA and chondroitin sulfate proteoglycans (CSPGs) inactivate integrins. Overexpressing kindlin-1 in dorsal root ganglion (DRG) neurons activates integrins, enabling their axons to overcome inhibitory molecules in the environment, and promoting regeneration in vivo following dorsal root crush. Other studies have indicated that expression of the talin head alone or with kindlin can enhance integrin activation. Here, using adult rat DRG neurons, we investigate the effects of overexpressing various forms of talin on axon growth and integrin signaling. We found that overexpression of the talin head activated axonal integrins but inhibited downstream signaling via FAK, and did not promote axon growth. Similarly, co-expression of the talin head and kindlin-1 prevented the growth-promoting effect of kindlin-1, suggesting that the talin head acts as a form of dominant negative for integrin function. Using full-length talin constructs in PC12 cells we observed that neurite growth was enhanced by the expression of wild-type talin and more so by two 'activated' forms of talin produced by point mutation (on laminin and aggrecan-laminin substrates). Nevertheless, co-expression of full-length talin with kindlin did not promote neurite growth more than either molecule alone. In vivo, we find that talin is present in PNS axons (sciatic nerve), and also in CNS axons of the corticospinal tract.

Incidence of pituitary dysfunction following traumatic brain injury: A prospective study from a regional neurosurgical centre.

Patients with traumatic brain injury (TBI) may develop pituitary dysfunction. Although, there is now increasing awareness of and investigations into such post-traumatic hypopituitarism (PTHP), the exact prevalence and incidence remain uncertain. Here, we aim to identify the incidence of PTHP in a selected population of TBI patients deemed at risk of PTHP at a regional neurosurgical centre in the UK. A total of 105 patients have been assessed in two cohorts: (i) 58 patients in serial cohort and (ii) 47 patients in cross-sectional late cohort. We found that in serial cohort, 10.3% (6/58) of TBI patients had abnormalities of the pituitary-adrenal axis in the acute phase (Day 0-7 post injury). In comparison, in cross-sectional late cohort, 21.3% (10/47) of the patients developed dysfunction in at least one of their pituitary axes at 6 months or more post-TBI, with hypogonadotrophic hypogonadism being the most common. Twenty-two patients from these two cohorts had their growth hormone assessment at 12 months or more post-TBI and 9.1% (2/22) were found to have growth hormone deficiency. Our results suggest that PTHP is a common condition amongst sufferers of TBI, and appropriate measures should be taken to detect and manage it.

Semaphorin 3A binds to the perineuronal nets via chondroitin sulfate type E motifs in rodent brains.

Chondroitin sulfate (CS) and the CS-rich extracellular matrix structures called perineuronal nets (PNNs) restrict plasticity and regeneration in the CNS. Plasticity is enhanced by chondroitinase ABC treatment that removes CS from its core protein in the chondroitin sulfate proteoglycans or by preventing the formation of PNNs, suggesting that chondroitin sulfate proteoglycans in the PNNs control plasticity. Recently, we have shown that semaphorin3A (Sema3A), a repulsive axon guidance molecule, localizes to the PNNs and is removed by chondroitinase ABC treatment (Vo, T., Carulli, D., Ehlert, E. M., Kwok, J. C., Dick, G., Mecollari, V., Moloney, E. B., Neufeld, G., de Winter, F., Fawcett, J. W., and Verhaagen, J. (2013) Mol. Cell. Neurosci. 56C, 186-200). Sema3A is therefore a candidate for a PNN effector in controlling plasticity. Here, we characterize the interaction of Sema3A with CS of the PNNs. Recombinant Sema3A interacts with CS type E (CS-E), and this interaction is involved in the binding of Sema3A to rat brain-derived PNN glycosaminoglycans, as demonstrated by the use of CS-E blocking antibody GD3G7. In addition, we investigate the release of endogenous Sema3A from rat brain by biochemical and enzymatic extractions. Our results confirm the interaction of Sema3A with CS-E containing glycosaminoglycans in the dense extracellular matrix of rat brain. We also demonstrate that the combination of Sema3A and PNN GAGs is a potent inhibitor of axon growth, and this inhibition is reduced by the CS-E blocking antibody. In conclusion, Sema3A binding to CS-E in the PNNs may be a mechanism whereby PNNs restrict growth and plasticity and may represent a possible point of intervention to facilitate neuronal plasticity.

Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration.

Growing and regenerating axons need to interact with the molecules in the extracellular matrix as they traverse through their environment. An important group of receptors that serve this function is the integrin superfamily of cell surface receptors, which are evolutionarily conserved αß heterodimeric transmembrane proteins. The function of integrins is controlled by regulating the affinity for ligands (also called "integrin activation"). Previous results have shown that CNS inhibitory molecules inactivate axonal integrins, while enhancing integrin activation can promote axon growth from neurons cultured on inhibitory substrates. We tested two related molecules, kindlin-1 and kindlin-2 (Fermitin family members 1 and 2), that can activate ß1, ß2, and ß3 integrins, for their effects on integrin signaling and integrin-mediated axon growth in rat sensory neurons. We determined that kindlin-2, but not kindlin-1, is endogenously expressed in the nervous system. Knocking down kindlin-2 levels in cultured sensory neurons impaired their ability to extend axons, but this was partially rescued by kindlin-1 expression. Overexpression of kindlin-1, but not kindlin-2, in cultured neurons increased axon growth on an inhibitory aggrecan substrate. This was found to be associated with enhanced integrin activation and signaling within the axons. Additionally, in an in vivo rat dorsal root injury model, transduction of dorsal root ganglion neurons to express kindlin-1 promoted axon regeneration across the dorsal root entry zone and into the spinal cord. These animals demonstrated improved recovery of thermal sensation following injury. Our results therefore suggest that kindlin-1 is a potential tool for improving axon regeneration after nervous system lesions.

Awake craniotomy for brain tumor resection: Patient experience and acceptance in an Asian population.

INTRODUCTION: Awake craniotomy is well-established for resection of brain tumor in the eloquent areas. Previous studies from Western countries have reported good level of patient tolerance and acceptance. However, its acceptability in non-Western populations, with different ethnic, social, cultural, religious, and linguistic backgrounds, has not been studied systematically. This study aims to evaluate the experience of patients from an Asian population who underwent awake craniotomy for tumor resection. METHODS: Data on patient experience were collected by interviewing patients using a structured questionnaire at follow-up appointment. Data on patient demographics and diagnosis were collected from medical records. RESULTS: Eighteen patients (age 16-68 years) who underwent 20 awake craniotomies were recruited. Preoperatively, all (100%) patients understood the indication for awake craniotomy. Almost all felt fully counseled by the neurosurgeon (90%), anesthetist (100%), and neuropsychologist (95%). Ninety-five percent reported their family to be supportive of awake craniotomy. Seventy-five percent felt adequately prepared on operation day. Intraoperatively, most patients did not experience pain/discomfort (55%) or anxiety (65%). Nearly all found intraoperative motor and language testing to be easy (100% and 90%, respectively). Postoperatively, 100% were satisfied with their care. One hundred percent rated their overall experience as good or excellent. Eighty percent were willing to undergo awake craniotomy again if indicated. CONCLUSION: Awake craniotomy is well-accepted in an Asian population. All patients had good-to-excellent overall experience, with most willing to undergo awake craniotomy again. Our findings underscore the generalizability of awake craniotomy across different socio-cultural backgrounds and support its utilization in countries with a significant Asian population.

Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling.

Chondroitin sulfate proteoglycans (CSPGs) are upregulated after CNS lesions, where they inhibit axon regeneration. In order for axon growth and regeneration to occur, surface integrin receptors must interact with surrounding extracellular matrix molecules. We have explored the hypothesis that CSPGs inhibit regeneration by inactivating integrins and that forcing integrins into an active state might overcome this inhibition. Using cultured rat sensory neurons, we show that the CSPG aggrecan inhibits laminin-mediated axon growth by impairing integrin signaling via decreasing phosphorylated FAK (pFAK) and pSrc levels, without affecting surface integrin levels. Forcing integrin activation and signaling by manganese or an activating antibody TS2/16 reversed the inhibitory effect of aggrecan on mixed aggrecan/laminin surfaces, and enhanced axon growth from cultured rat sensory neurons (manganese) and human embryonic stem cell-derived motoneurons (TS2/16). The inhibitory effect of Nogo-A can also be reversed by integrin activation. These results suggest that inhibition by CSPGs can act via inactivation of integrins, and that activation of integrins is a potential method for improving axon regeneration after injury.

Predictors of 30-day postoperative systemic complications in geriatric patients undergoing elective brain tumor surgery.

Little evidence exists to guide the preoperative selection of elderly brain tumor patients who are fit for surgery. We aimed to evaluate the safety of brain tumor resection in geriatric patients and identify predictors of postoperative 30-day systemic complications. We conducted a retrospective cohort study of 212 consecutive patients at or above the age of 60 years who underwent elective brain tumor resection between 2007 and 2017. The primary outcome measures analyzed were perioperative systemic complications within 30 days after the operation. A total of 212 geriatric brain tumor patients were included. Fifty-two (24.5%) had a 30-day systemic complication. Among them, 29 (13.7%) had systemic infections, 13 (6.1%) had perioperative seizures, 10 (4.7%) had syndrome of inappropriate antidiuretic hormone secretion (SIADH), five (2.4%) had deep venous thrombosis (DVT), four (1.9%) had perioperative stroke, three (1.4%) had acute myocardial infarction (AMI) and three (1.4%) had central nervous system (CNS) infections. One patient (0.5%) died. Perioperative stroke was predicted by previous stroke (p = 0.040), chronic liver disease (p < 0.001) and vestibular schwannoma (p = 0.002 with reference to meningiomas). Perioperative AMI was predicted by co-existing ischemic heart disease (p = 0.031). Systemic infection was predicted by female gender (p = 0.007) and preoperative Karnofsky Performance Scale (KPS) score < 70 (p = 0.019). DVT was predicted by GBM (p = 0.014). In conclusion, brain tumor surgery can be safe in carefully-selected geriatric patients. The risk factors identified in this study would be helpful to select suitable candidates for surgery.

Challenges in the Management of a Ruptured Bihemispheric Posterior Inferior Cerebellar Artery Aneurysm.

BACKGROUND: Bihemispheric posterior inferior cerebellar artery (PICA) is a rare anatomic variant wherein a single PICA supplies both cerebellar hemispheres. Inasmuch as it is the only PICA, treatment of aneurysms arising from this anatomic variant is more complex. We present a case of a ruptured bihemispheric PICA aneurysm and the challenges encountered in its management. CASE DESCRIPTION: A 54-year-old man presented with giddiness and nausea. Otherwise, he was neurologically intact. Computed tomography of the brain showed a right cerebellar hematoma and intraventricular hemorrhage. Cerebral angiography revealed a dissecting aneurysm in the retromedullary segment of a right bihemispheric PICA with a prominent saccular component. Initially, the patient refused to undergo any invasive treatment. However, when a follow-up angiogram showed an increase in the size of the aneurysm sac, he consented to treatment. Although parent vessel occlusion (PVO) was the clinical recommendation, in view of the patient's apprehensions, only the saccular component of the aneurysm was coil embolized without sacrifice of the parent vessel. Fifteen days after the coiling, there was a rebleed from this dissecting aneurysm, which was treated with PVO followed by suboccipital craniectomy. The patient made a reasonable recovery, and his modified Rankin score was 1 at his 6-month follow-up visit. CONCLUSIONS: In dissecting aneurysms of a bihemispheric PICA, isolated endosaccular occlusion provides uncertain protection from a rebleed, whereas a more reliable treatment with PVO carries an unpredictable risk of ischemic complications. The risks of a PVO may be rationalized as a life-saving measure; however, the subsequent threshold for posterior fossa decompression should be low.

The role of local protein synthesis and degradation in axon regeneration.

In axotomised regenerating axons, the first step toward successful regeneration is the formation of a growth cone. This requires a variety of dynamic morphological and biochemical changes in the axon, including the appearance of many new cytoskeletal, cell surface and signalling molecules. These changes suggest the activation of coordinated complex cellular processes. A recent development has been the demonstration that the regenerative ability of some axons depends on their capacity to locally synthesise new proteins and degrade others at the injury site autonomously from the cell body. There are also events involving the degradation of cytoskeletal and other molecules, and activation of signalling pathways, with axotomy-induced calcium changes probably being an initiating event. A future challenge will be to understand how this complex network of processes interacts in order to find therapeutic ways of promoting the regeneration of CNS axons.

Cytoplasmic polyadenylation and cytoplasmic polyadenylation element-dependent mRNA regulation are involved in Xenopus retinal axon development.

BACKGROUND: Translation in axons is required for growth cone chemotropic responses to many guidance cues. Although locally synthesized proteins are beginning to be identified, how specific mRNAs are selected for translation remains unclear. Control of poly(A) tail length by cytoplasmic polyadenylation element (CPE) binding protein 1 (CPEB1) is a conserved mechanism for mRNA-specific translational regulation that could be involved in regulating translation in axons. RESULTS: We show that cytoplasmic polyadenylation is required in Xenopus retinal ganglion cell (RGC) growth cones for translation-dependent, but not translation-independent, chemotropic responses in vitro, and that inhibition of CPE binding through dominant-negative interference severely reduces axon outgrowth in vivo. CPEB1 mRNA transcripts are present at low levels in RGCs but, surprisingly, CPEB1 protein was not detected in eye or brain tissue, and CPEB1 loss-of-function does not affect chemotropic responses or pathfinding in vivo. UV cross-linking experiments suggest that CPE-binding proteins other than CPEB1 in the retina regulate retinal axon development. CONCLUSION: These results indicate that cytoplasmic polyadenylation and CPE-mediated translational regulation are involved in retinal axon development, but that CPEB1 may not be the key regulator of polyadenylation in the developing retina.