p-tau Ser356 is associated with Alzheimer's disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003.

Tau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. Tau can be phosphorylated at up to 85 different sites, and there is increasing interest in whether tau phosphorylation at specific epitopes, by specific kinases, plays an important role in disease progression. The AMP-activated protein kinase (AMPK)-related enzyme NUAK1 has been identified as a potential mediator of tau pathology, whereby NUAK1-mediated phosphorylation of tau at Ser356 prevents the degradation of tau by the proteasome, further exacerbating tau hyperphosphorylation and accumulation. This study provides a detailed characterisation of the association of p-tau Ser356 with progression of Alzheimer's disease pathology, identifying a Braak stage-dependent increase in p-tau Ser356 protein levels and an almost ubiquitous presence in neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that p-tau Ser356 co-localises with synapses in AD postmortem brain tissue, increasing evidence that this form of tau may play important roles in AD progression. To assess the potential impacts of pharmacological NUAK inhibition in an ex vivo system that retains multiple cell types and brain-relevant neuronal architecture, we treated postnatal mouse organotypic brain slice cultures from wildtype or APP/PS1 littermates with the commercially available NUAK1/2 inhibitor WZ4003. Whilst there were no genotype-specific effects, we found that WZ4003 results in a culture-phase-dependent loss of total tau and p-tau Ser356, which corresponds with a reduction in neuronal and synaptic proteins. By contrast, application of WZ4003 to live human brain slice cultures results in a specific lowering of p-tau Ser356, alongside increased neuronal tubulin protein. This work identifies differential responses of postnatal mouse organotypic brain slice cultures and adult human brain slice cultures to NUAK1 inhibition that will be important to consider in future work developing tau-targeting therapeutics for human disease.

Survival and complications following supra- and infratentorial brain metastasis resection.

OBJECTIVE: 15-30% of primary cancers metastasise to the brain. Of these, 10-25% involve the posterior fossa. It remains unclear whether patients undergoing resection for infratentorial brain metastases experience poorer prognosis than those with supratentorial lesions. We compare the post-operative outcomes of these two groups. METHODS: We searched the electronic health records of all patients undergoing brain metastases resection at our regional neurosurgical centre between February 2014 and August 2019. Clinical data was collected on 85 consecutive patients (61 supratentorial, 24 infratentorial metastases). Outcome measures included overall survival, post-operative complications, and performance status. Patients were followed up until 21/04/2020. RESULTS: Median post-operative survival of patients with supratentorial metastases was 323 days (95% CI 235-411), compared to 277 days (95% CI 195-359) for those with infratentorial metastases. These two groups experienced comparable survival (log rank = 0.276, p = 0.60) on univariate analysis. Infratentorial metastasis location was not associated with a change in survival using a Cox proportional hazards model incorporating age, sex and extracranial disease activity (HR = 1.39, 95% CI 0.777-2.486) (p = 0.27). However, neurological and non-neurological post-operative complications were more frequent in patients with infratentorial metastases (neurological = 21% vs 13%, non-neurological = 25% vs 2%, p = 0.002). CONCLUSION: Patients with supra- and infratentorial metastases experienced comparable post-operative survival but posterior fossa metastasis location was associated with a 2.5 times higher risk of neurological and/or non-neurological post-operative complications. A better understanding of the precise indications for safe and effective surgical intervention for posterior fossa metastases is required.

Craniotomy for recurrent glioblastoma: Is it justified? A comparative cohort study with outcomes over 10 years.

OBJECTIVE: The role of repeat resection for recurrent glioblastoma multiforme (rGBM) is unclear. This large comparative cohort study assessed overall survival (OS), survival since recurrence (SSR), quality of life, and complications in reoperated versus non-reoperated patients for rGBM. PATIENTS AND METHODS: All patients with rGBM between 2005 and 2015, who were discussed by our institution's multi-disciplinary team, and who either did or did not undergo reoperation, were prospectively followed up with data collected and compared. Survival and prognostic factors were analysed using Kaplan-Meier and Cox regression methods. RESULTS: 312 patients (reoperated, n = 145; non-reoperated, n = 167) were analysed. Median SSR was 10.8 months and 6.9 months in the reoperated and non-reoperated groups respectively (Log-rank test: p = 0.02). Median OS was 24.1 months and 20.4 months in the reoperated and non-reoperated groups, respectively (Log-rank test: p = 0.04). Quality of life as measured by Short Form 36 scores were 59 versus 54 at baseline and 62 versus 51 at four-month follow-up for re-operated and non-reoperated groups, respectively (p < 0.05). Age < 60 years, Karnofsky Performance Status (KPS) ≥ 80, recurrence ≥ 9 months from initial diagnosis, methylguanine methyltransferase (MGMT) promoter methylation, and extent of resection (EOR) > 80 %, each were significant predictors of SSR and OS. Complication rates were 5.5 % and 6.2 % following repeat resection and primary resection, respectively (p > 0.05). CONCLUSION: This is the first large prospective comparative cohort study of rGBM and demonstrates that repeat resection confers a small but significant benefit in survival and quality of life over non-operative treatment. Best prognosis is associated with: younger age, KPS ≥ 80, late recurrence, MGMT promoter methylation and EOR > 80 %.

Mental incapacity in patients undergoing neuro-oncologic treatment: a cross-sectional study.

OBJECTIVE: To evaluate the prevalence of mental incapacity to make neuro-oncologic treatment decisions and to identify patients likely to experience difficulty with medical decision-making to enable a more rigorous and focused assessment. METHODS: The preoperative mental capacity to give valid consent to neurosurgery of 100 patients with radiologically suspected intracranial tumors was assessed. Mental capacity was formally assessed using the MacArthur Competence Assessment Tool for Treatment (MACCAT-T) conducted by a dual-qualified physician and lawyer. To assess the relationship between cognition and mental capacity, cognitive function was assessed after the MACCAT-T interview using the Addenbrooke's Cognitive Examination-revised (ACE-R). Decisions about capacity made by the assessor were compared with the informal assessment of capacity of the neurosurgical team. RESULTS: Of 100 patients, 25 were identified by the assessor as lacking the necessary mental capacity to give valid consent to neurosurgery. Mental incapacity was most common among patients with World Health Organization grade IV tumors (38%) and was more common in men than women (36% of men lacked capacity vs 14% of women). Patients lacking mental capacity were significantly more cognitively impaired than those with capacity (median [interquartile range (IQR)] total ACE-R of 44 [0, 65.5] for incapable patients compared with a median [IQR] total ACE-R score of 88 [82, 95] for patients with capacity). Of 25 patients found to lack capacity by the assessor, 13 (52%) were identified as lacking capacity by the neurosurgical team and were treated under the provisions of the Adults with Incapacity (Scotland) Act 2000. A score of <4/7 in the semantic verbal fluency subset of the ACE-R (naming up to 10 animals in 1 minute) was predictive of incapacity (96% sensitivity, 63% specificity). CONCLUSIONS: Mental incapacity in patients with intracranial tumors is common and is underestimated by clinicians seeking consent for neuro-oncologic treatment. Cognitive impairment is associated with incapacity. We propose a simple, brief cognitive screening test to identify patients who warrant a more rigorous interrogation of their mental capacity as part of the process of seeking consent for neuro-oncologic treatment.

Paediatric and adult vascular intracranial complications of sickle-cell disease.

BACKGROUND: To enumerate possible intracranial vascular sequelae of sickle-cell disease, to identify risk factors and outline management strategies. METHOD: Retrospective review of a single unit experience managing vascular intracranial complications of sickle-cell disease from 1995 until 2005. Information such as homozygosity/heterozygosity, duration of disease, disease control as indicated by haematology follow-up, concurrent sickle-cell disease (SCD)-related health problems and neurosurgical management was recorded. The pattern of vascular disease was analysed to reveal possible contributory/risk factors towards development of vascular intracranial complications. SUBJECTS: All patients presenting with vascular intracranial complications of sickle-cell disease from 1995 to 2005 were evaluated. OUTCOME MEASURES: Classification of vascular intracranial complications into one or more of the following categories: aneurysmal subarachnoid haemorrhage, non-aneurysmal subarachnoid/intraventricular haemorrhage and vasculitis. FINDINGS: There were ten patients in the study. All symptomatic vascular intracranial complications of SCD requiring neurosurgical intervention were homozygous for SCD. Aneurysms were likely to be multiple. Ruptured aneursyms in SCD were small (average 4 mm). There was a propensity for aneurysms to occur in the posterior circulation, in particular the posterior cerebral artery was frequently involved. Patients with aneurysms and Moyamoya-type vasculitis were likely to have occlusive disease of the internal carotid arteries. CONCLUSIONS: The vascular intracranial complications of sickle-cell disease have an aggressive natural history. Tight control of SCD may reduce the possibility of complications. Complications that arise should be managed in the context of the disease entity rather than in isolation. Consideration should be given to bypass procedures, parent vessel ligations and revascularization techniques. Transcranial Doppler may be used to identify SCD patients with cerebrovascular occlusive disease, who may have increased risk of aneurysmal rupture.

Effect of apolipoprotein E genotype on hematoma volume after trauma.

OBJECT: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is associated with poor outcome after head injury and spontaneous intracerebral hemorrhage (SICH). The aims of this study were to determine if patients in whom one or more APOE-epsilon4 alleles are present are more likely to sustain intracranial mass lesions after head injury and to determine whether there is an isoform-specific effect on the size of the intracranial hematoma. METHODS: The authors performed a computerized volumetric analysis of 142 hematomas visible on computerized tomography (CT) scans obtained in 129 patients. The APOE genotype was determined by subjecting buccal smear samples to polymerase chain reaction and restriction enzyme digestion. Allele frequencies were similar in head-injured patients with and without intracranial hematomas (p = 0.36). Univariate analysis revealed that in those patients with one or more APOE-epsilon4 alleles hematoma volume was greater (cube root-transformed values) than that found in patients without the APOE-epsilon4 allele (3.1 cm compared with 2.5 cm, p = 0.0039). The results of univariate analysis also suggested significant effects of patient age, injury severity (mild, moderate, or severe according to admission Glasgow Coma Scale scores) and hematoma location (extraaxial, intraaxial, or both) on hematoma volume. The mechanism of injury (assault, fall, or other) was marginally associated with hematoma volume (p = 0.052). Time from injury to CT scan, hypoxia, and hypotension had no significant effect on hematoma volume. The results of multiple linear regression analysis showed that the presence of an APOE-epsilon4 allele and an extraaxial hematoma location were independent predictors of hematoma volume, after adjusting for patient age, hours between injury and CT scan, injury severity, and injury mechanism. CONCLUSIONS: Larger hematomas were found in head-injured patients with one or more APOE-epsilon4 alleles than in patients without the allele. This may contribute to the poorer outcomes observed in these patients.