Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.

Management of brain tumour related epilepsy (BTRE): a narrative review and therapy recommendations.

Brain Tumour Related Epilepsy (BTRE) has a significant impact on Quality of Life with implications for driving, employment, and social activities. Management of BTRE is complex due to the higher incidence of drug resistance and the potential for interaction between anti-cancer therapy and anti-seizure medications (ASMs). Neurologists, neurosurgeons, oncologists, palliative care physicians and clinical nurse specialists treating these patients would benefit from up-to-date clinical guidelines. We aim to review the current literature and to outline specific recommendations for the optimal treatment of BTRE, encompassing both Primary Brain Tumours (PBT) and Brain Metastases (BM). A comprehensive search of the literature since 1995 on BTRE was carried out in PubMed, MEDLINE and EMCARE. A broad search strategy was used, and the evidence evaluated and graded based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Seizure frequency varies between 10 and 40% in patients with Brain Metastases (BM) and from 30% (high-grade gliomas) to 90% (low-grade gliomas) in patients with PBT. In patients with BM, risk factors include number of BM and melanoma histology. In patients with PBT, BTRE is more common in patients with lower grade histology, frontal and temporal tumours, presence of an IDH mutation and cortical infiltration. All patients with BTRE should be treated with ASMs. Non-enzyme inducing ASMs are recommended as first line treatment for BTRE, but up to 50% of patients with BTRE due to PBT remain resistant. There is no proven benefit for the use of prophylactic ASMs, although there are no randomised trials testing newer agents. Surgical and oncological treatments i.e. radiotherapy and chemotherapy improve BTRE. Vagus Nerve Stimulation has been used with partial success. The review highlights the relative dearth of high-quality evidence for the management of BTRE and provides a framework for further studies aiming to improve seizure control, quality of life, and indications for ASMs.KEY POINTSOffer levetiracetam or lamotrigine to all patients with primary or metastatic brain tumours who have seizure(s), irrespective of whether these are partial or generalised.ASM withdrawal for patients in remission is not recommended due to high rates of seizure recurrence.ASM prophylaxis is not generally recommended in the management of seizure-naïve patients.Both levetiracetam and lamotrigine are safe in pregnancy and breastfeeding.

Radiation and the nervous system.

Radiation therapy is widely used for benign and malignant brain tumours as it is effective and well tolerated. However, damage to the surrounding healthy nervous system tissue leads to a variety of complications both in the short term and long term, ranging from mild and self-limiting to irreversible and fatal. Radiation neurotoxicity is due to a combination of early inflammation and oligodendroglial damage followed later by brain tissue necrosis, white matter damage, accelerated vascular disease and the development of secondary tumours. This article explains the basic principles of radiation physics, the different modalities used in clinical practice, how radiotherapy is planned and delivered and the scientific basis of radiation damage. The main body of the article focuses on the clinical features of radiation toxicity in the brain, spinal cord, cranial and peripheral nerves with an emphasis on the distinction between early and delayed complications.

Eligibility to drive and neurology: the how and the why.

Driving is an integral part of adult life and losing a driving licence is potentially a major problem. Many neurological conditions may impact on driving, either by increasing the risk of a sudden disabling event or by affecting cognition, vision, reaction speed, motor coordination, peripheral sensation or visuospatial processing. In the UK, the Drivers Medical Group of the Driver and Vehicle Licensing Agency (DVLA) decides whether an individual's medical condition meets the appropriate standards for driving. The licensing decision rests with the DVLA and is not at the clinician's discretion. However, clinicians must inform patients of their legal obligations towards the DVLA and how their neurological symptoms may restrict their driving. We discuss risk assessment, how chronic disabling neurological disease may impact on driving and the general principles of applying medical standards for fitness to drive. We also highlight how legal driving eligibility varies around the world. Finally, we discuss the practical applications relating to a specific case.

Longitudinal structural and perfusion MRI enhanced by machine learning outperforms standalone modalities and radiological expertise in high-grade glioma surveillance.

PURPOSE: Surveillance of patients with high-grade glioma (HGG) and identification of disease progression remain a major challenge in neurooncology. This study aimed to develop a support vector machine (SVM) classifier, employing combined longitudinal structural and perfusion MRI studies, to classify between stable disease, pseudoprogression and progressive disease (3-class problem). METHODS: Study participants were separated into two groups: group I (total cohort: 64 patients) with a single DSC time point and group II (19 patients) with longitudinal DSC time points (2-3). We retrospectively analysed 269 structural MRI and 92 dynamic susceptibility contrast perfusion (DSC) MRI scans. The SVM classifier was trained using all available MRI studies for each group. Classification accuracy was assessed for different feature dataset and time point combinations and compared to radiologists' classifications. RESULTS: SVM classification based on combined perfusion and structural features outperformed radiologists' classification across all groups. For the identification of progressive disease, use of combined features and longitudinal DSC time points improved classification performance (lowest error rate 1.6%). Optimal performance was observed in group II (multiple time points) with SVM sensitivity/specificity/accuracy of 100/91.67/94.7% (first time point analysis) and 85.71/100/94.7% (longitudinal analysis), compared to 60/78/68% and 70/90/84.2% for the respective radiologist classifications. In group I (single time point), the SVM classifier also outperformed radiologists' classifications with sensitivity/specificity/accuracy of 86.49/75.00/81.53% (SVM) compared to 75.7/68.9/73.84% (radiologists). CONCLUSION: Our results indicate that utilisation of a machine learning (SVM) classifier based on analysis of longitudinal perfusion time points and combined structural and perfusion features significantly enhances classification outcome (p value= 0.0001).

Peripheral nerve neurolymphomatosis: Clinical features, treatment, and outcomes.

This series characterises nine patients with neurohistopathologically proven peripheral nerve neurolymphomatosis. A search of the hospital neuropathology database from 2002 to 2019 identified biopsy proven cases. Clinical data, investigation modalities, treatments, and outcomes were collated. Median age at neuropathy onset was 47 y, the neuropathy commonly as the initial lymphoma disease manifestation. Most (8/9) presented with painful asymmetrical sensory disturbance, with additional cranial nerve involvement in three. Neurophysiology typically demonstrated multiple axonal mononeuropathies. Cerebrospinal fluid protein was often raised (6/8). Magnetic resonance imaging suggested peripheral nerve infiltration in 6/9 and positron emission tomography CT in 4/9. Bone marrow biopsy was abnormal in 6/8. Treatment involved systemic or intrathecal chemotherapy and radiotherapy. Median survival was 23 mo. Neurolymphomatosis is a rare but important cause of neuropathy, particularly in those lacking systemic evidence of lymphoma as correct aggressive treatment can prolong survival. Nerve biopsy is essential to classify lymphoma type and rule out alternatives.

Neurotoxicity-CAR T-cell therapy: what the neurologist needs to know.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most innovative therapies for haematological malignancies to emerge in a generation. Clinical studies have shown that a single dose of CAR T-cells can deliver durable clinical remissions for some patients with B-cell cancers where conventional therapies have failed.A significant complication of CAR therapy is the immune effector cell-associated neurotoxicity syndrome (ICANS). This syndrome presents a continuum from mild tremor to cerebral oedema and in a minority of cases, death. Management of ICANS is mainly supportive, with a focus on seizure prevention and attenuation of the immune system, often using corticosteroids. Parallel investigation to exclude other central nervous system pathologies (infection, disease progression) is critical. In this review, we discuss current paradigms around CAR T-cell therapy, with a focus on appropriate investigation and management of ICANS.

The impact of route of diagnosis on survival in patients with glioblastoma.

INTRODUCTION: The standard of care for glioblastoma is maximal debulking surgery followed by chemo-radiotherapy (CRT). Published data show worse outcomes for patients who present with GBM as an emergency. This study investigates prognostic factors in a cohort of GBM patients treated with postoperative CRT, and compares outcomes in patients who present via emergency pathways with those who present through outpatient clinics. METHODS: Patients with GBM operated on between 1 April 2010 and 5 October 2015 and then treated with postoperative CRT were included in the study. Data were collected from electronic patient records and radiotherapy planning systems. Survival data were censored on 22 March 2016. Univariate and multivariate analyses of prognostic factors were performed. RESULTS: 104 patients were studied; mean age 51.6 years (range 19 to 70 years). Median overall survival (OS) was 16.5 months, with 68.2% and 37.8% alive at 12 and 24 months respectively. On multivariate analysis, improved OS was associated with ECOG Performance Status of 0 (vs ≥1; p = .012), patient age <60 years (vs ≥60 years; p < .001), and surgical debulking or macroscopic complete resection (vs biopsy; p < .001). Patients who presented through emergency medical pathways had worse survival (p = .005). CONCLUSION: This study supports published data that initial presentation through emergency pathways is associated with worse outcomes in GBM, even in patients who remain fit enough to receive post-operative CRT.

Acute demyelination following radiotherapy for glioma: a cautionary tale.

Radiotherapy is the mainstay of treatment after surgery for high-grade gliomas and is usually well tolerated. Radiation toxicity in the brain is usually classified according to the timing of side effects in relation to treatment, as either acute (during radiotherapy), early delayed (within 12 weeks of radiotherapy) or late delayed (months to years after radiotherapy). We report two cases of young women who developed severe acute demyelination within 4 months of radiotherapy for glioma, one of whom had a previous history of transverse myelitis. Both improved with corticosteroids and remain in tumour remission. These cases emphasise the importance of careful discussion with patients before starting radiotherapy if there is a previous history of central nervous system demyelination or multiple white matter lesions on MRI.

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. FINDINGS: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. INTERPRETATION: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. FUNDING: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Retrospective Study of the Survival and Patient Satisfaction with Composite Dahl Restorations in the Management of Localised Anterior Tooth Wear.

OBJECTIVE: This retrospective study was undertaken to evaluate the clinical performance of direct composite restorations placed at an increased vertical dimension to manage localised anterior tooth wear using the Dahl approach. SUBJECTS AND METHODS: Two hundred and ninety six restorations were placed at an increased OVD in 41 subjects with localized anterior Tooth Surface Loss (TSL) were included. Survival analysis was carried out at three levels, major failure only, minor failure only and all types of failure. Clinical follow up showed that the posterior occlusion was reformed after a mean duration of 25.4 months (range 6 to 60 months). Mean clinical follow up of 25.4 months showed a success rate of 88.8% and survival rate of 95.6% of the restorations. The major failure rate was 4.4% while the minor failure rate was 8.7%. Patients' reported a significant improvement in appearance, and self-confidence and reduction in sensitivity. Self-reported patient satisfaction with the procedure was high. CLINICAL RELEVANCE: Placement of resin-based composite restorations at an increased occlusal vertical dimension to manage localised anterior tooth wear has a good short to medium term survival.

Diagnostic delay and survival in high-grade gliomas - evidence of the 'waiting time paradox'?

INTRODUCTION: We present a retrospective single-centre study to determine whether delays in diagnosis of high-grade glioma (HGG) impact on overall survival (OS). MATERIAL AND METHODS: Consecutive patients diagnosed with HGG at a single neuroscience centre in 2011 were reviewed. Route of referral and time from initial presentation to diagnosis were analysed and correlated with OS. RESULTS: 118 patients were studied - 92 patients with glioblastoma (GBM). Diagnosis of GBM in patients presenting to emergency services was quicker than that through outpatients (8 days vs. 26 days, p < 0.0001), but these patients had significantly worse OS (181 days vs. 386 days p = 0.0075). This trend was observed for the whole cohort (Grade III and GBM), with OS 278 days in patients presenting to emergency services compared with 423 days for patients presenting via outpatients (p = 0.0034). Patients presenting to outpatients were younger (median age: 54 years) compared with patients presenting to emergency services (median age: 62.5 years) (p = 0.0106). There were no other differences between the two groups with respect to the nature of presenting symptoms. CONCLUSION: Earlier diagnosis is paradoxically associated with a worse OS in GBM. An 'aggressive' phenotype with rapid symptomatic deterioration and hence emergency presentation is a poor prognostic factor not influenced by earlier diagnosis.

Failure Mechanisms of Fibre Posts: A Literature Review.

AIM: To review the available evidence for the causes of failure of fibre posts. MATERIALS AND METHOD: A search of MEDLINE was conducted to retrieve available data on fibre posts used for restoration of endodontically treated teeth since 1980. The Cochrane Library was also separately searched for systematic reviews. Additionally, references of the retrieved articles were also hand searched for further relevant papers. All the selected papers were then critically appraised subject to meeting inclusion criteria. RESULTS: Nineteen prospective clinical trials were included after critical appraisal of the papers. Causes of failure of fibre posts were identified as follows: adhesive failure, root fracture, post fracture, endodontic failure, secondary caries and periodontal complications. Risk factors for each of the failures were investigated and evidence-based recommendations for minimising these complications are discussed. CONCLUSION: Although laboratory studies showed favourable mechanical and physical properties of fibre posts, clinically, there has been a wide range of failures mechanisms are reported in the literature. Adhesive failure was reported in 16 of the 19 trials, making it the most frequent cause of failure. The available evidence does not indicate a difference in short-term survival probability between metal or fibre posts. A number of risk factors, which affect the longevity of fibre posts, were identified and discussed. Since there is considerable heterogeneity in study designs and reported survival rates of included studies, longer-term well-designed standardised clinical trails are required.

Brain tumour mimics and chameleons.

The timely diagnosis of a brain tumour is crucial to optimising outcome in a group of patients with limited survival. Several common neurological conditions mimic brain tumours, causing concern to patient and physician until the correct diagnosis becomes clear. In addition, atypical presentations of brain tumours may cause diagnostic confusion, acting as chameleons and delaying correct workup and treatment. This review focuses on the important mimics and chameleons encountered in clinical practice, aiming to illustrate the wide range of clinical neurology encountered in this specialty and to provide guidance on reaching the correct diagnosis.

Clinical, Imaging and Neurogenetic Features of Patients with Gliomatosis Cerebri Referred to a Tertiary Neuro-Oncology Centre.

INTRODUCTION: Gliomatosis cerebri describes a rare growth pattern of diffusely infiltrating glioma. The treatment options are limited and clinical outcomes remain poor. To characterise this population of patients, we examined referrals to a specialist brain tumour centre. METHODS: We analysed demographic data, presenting symptoms, imaging, histology and genetics, and survival in individuals referred to a multidisciplinary team meeting over a 10-year period. RESULTS: In total, 29 patients fulfilled the inclusion criteria with a median age of 64 years. The most common presenting symptoms were neuropsychiatric (31%), seizure (24%) or headache (21%). Of 20 patients with molecular data, 15 had IDH wild-type glioblastoma, with an IDH1 mutation most common in the remainder (5/20). The median length of survival from MDT referral to death was 48 weeks (IQR 23 to 70 weeks). Contrast enhancement patterns varied between and within tumours. In eight patients who had DSC perfusion studies, five (63%) had a measurable region of increased tumour perfusion with rCBV values ranging from 2.8 to 5.7. A minority of patients underwent MR spectroscopy with 2/3 (66.6%) false-negative results. CONCLUSIONS: Gliomatosis imaging, histological and genetic findings are heterogeneous. Advanced imaging, including MR perfusion, could identify biopsy targets. Negative MR spectroscopy does not exclude the diagnosis of glioma.

White matter integrity assessed by diffusion tensor tractography in a patient with a large tumor mass but minimal clinical and neuropsychological deficits.

Diffusion tensor imaging (DTI) tractography and image registration were used to investigate a patient with a massive left-sided brain tumor, whose size was largely disproportionate to his subtle neurological deficits. MRI was obtained from the patient and his healthy identical twin, who acted as anatomical reference for DTI and as a control for quantitative measures. To compensate for the patient's altered anatomy, seed and way points for probabilistic tractography were drawn on the color-coded direction maps of the healthy twin. Registration, based on the combination of b0-images, T2-weighted and T1-weighted images, was used to identify the corresponding regions in the patient. The corticospinal tract (CST), the superior longitudinal fasciculus (SLF), and the cingulum bundle (CB) showed displaced anatomy. A significant difference was found between fractional anisotropy distribution along the left SLF and CB, but not along the CST. These findings fit well with the patient's substantial preservation of his motor abilities, while abnormalities of the SLF and CB could explain the subtle but detectable cognitive deficits.

Quantitative magnetisation transfer imaging in glioma: preliminary results.

Quantitative magnetisation transfer imaging (qMTI) is an extension of conventional MT techniques and allows the measurement of parameters that reflect tissue ultrastructure through the properties of macromolecule-bound protons; these include the bound proton fraction and the relaxation times of free and bound proton pools. It has been used in multiple sclerosis and Alzheimer's disease, and has shown changes in some of the parameters, particularly the bound proton fraction. The purpose of this pilot study was to assess whether qMTI could distinguish between gliomas and normal brain tissue, and provide proof of principle for its use in tumour characterisation. Eight subjects [three men, five women; mean age, 44 years; range, 27-66 years; seven World Health Organization (WHO) Grade II, one Grade III] with biopsy-proven glioma were imaged with a structural MRI protocol that included three-dimensional qMTI. qMTI parameters were extracted from regions of interest selected from different tumour components visible on conventional MR sequences, normal-appearing peritumoral tissue and distant normal-appearing white matter. All patients gave informed consent and the study was approved by the Local Research Ethics Committee. Almost all of the qMTI parameters detected abnormalities in both glioma and the peritumoral region relative to the distant white matter. In particular, the bound proton fraction was reduced significantly from 6.0 percentage units (pu) [standard deviation (SD), 0.5 pu] in normal-appearing white matter to 1.7 pu (SD = 0.5 pu) in solid tumour and 2.2 pu (SD = 0.5 pu) in peritumoral areas. This work shows that qMTI reveals abnormalities, not only in glioma, but also in the apparently normal tissue surrounding the conventionally defined tumour. Thus, qMTI shows promise for tumour characterisation and for studying tumour boundaries. These preliminary data justify larger studies in a range of different tumour types and grades.

A prospective study of the prevalence of periapical pathology in severely worn teeth.

UNLABELLED: The aim of this article was to carry out a prospective audit on a convenience sample of all new patients referred to the toothwear clinic at Cardiff University Dental Hospital to establish the prevalence of undiagnosed periapical pathology. CLINICAL RELEVANCE: The low prevalence value for undiagnosed periapical pathology in patients with advanced toothwear suggests that, for many patients, toothwear is a slow process which allows the defence mechanisms of the pulp to counteract the effects of wear. It also questions the necessity of taking routine radiographs of teeth with wear into dentine, in the absence of clinical symptoms. This would reduce the total radiation dose delivered to the patient and preserve valuable healthcare resources.

A case study investigating the role of the anterior temporal lobes in general semantics and semantics specific to persons, emotions and social conceptual knowledge.

The role of the anterior temporal lobes (ATLs) in semantic representation remains still much debated. Long thought to support domain-general semantic processing, recent accounts have alternatively suggested that they may be preferentially involved in the processing of person-related semantic knowledge. Several studies have supported such a distinction, but few have either examined both types of semantic processing together, or considered the role of potentially important confounding variables. Here, we address these issues by investigating both domain-general and person-specific semantic processing in a patient with focal ATL damage. The patient presents with dense anterograde and retrograde amnesia. Performance was impaired on tests of general semantic knowledge, but most striking deficits were for person-related semantics, including recognition and identification, knowledge of emotions and social conceptual knowledge. This unique case provides compelling evidence that, in addition to the role in general semantic knowledge, the ATLs are critical for person-related semantics.