Michael Buckland

Michael Buckland
Royal Prince Alfred Hospital | RPA · Department of Pathology Services

About

192
Publications
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Publications

Publications (192)
Article
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Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, va...
Article
Full-text available
Chronic traumatic encephalopathy (CTE) is a progressive tauopathy causally linked to repetitive mild traumatic brain injury. Currently, there are no established clinical diagnostic criteria for CTE, making post-mortem neuropathological examination essential for diagnosis. The pathological hallmark of CTE is the presence of perivascular neuronal p-t...
Article
Full-text available
The promise of urinary extracellular vesicles (uEVs) in biomarker discovery is emerging. However, the characteristics and compositions of different uEV subpopulations across normal physiological and pathological states require rigorous explication. We recently reported proteomic signatures of small (s)‐uEVs (<200 nm membranous nanoparticles) and de...
Preprint
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Background Head impacts, particularly, non-concussive impacts, are common in sport. Yet, their effects on the brain are poorly understood. Here, we investigated the acute effects of non-concussive impacts on brain microstructure, chemistry, and function using magnetic resonance imaging (MRI) and other techniques. Results Fifteen healthy male socce...
Article
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Simple Summary The MGMT gene is responsible for repairing DNA damage, including as a result of chemotherapy, and, therefore, antagonizes its effects. If the MGMT gene is ‘silenced’, there is defective DNA repair leading to increased chemotherapy-related tumor cell death. MGMT gene silencing can occur through a process called ‘promoter methylation’....
Preprint
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Glioblastoma (GBM) is an aggressive primary brain tumor with a dismal prognosis. Given the paucity of tumor infiltrating lymphocytes (TILs), an immune suppressive tumor microenvironment and a low tumor mutation burden, the potential benefits of immune checkpoint inhibition (ICI) for GBM patients are considered low 1,2 . Anti-PD-1 ICI monotherapy ad...
Article
A 32-year-old female with advanced human immunodeficiency virus infection presented to an Australian hospital with subacute, worsening symptoms of encephalitis. Metagenomic sequencing and Dengue NS3 antigen staining of brain tissue confirmed active dengue virus (DENV) encephalitis. The most recent possible DENV exposure was months prior in West Afr...
Article
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Background Biomarkers that reflect glioblastoma tumour activity and treatment response are urgently needed to help guide clinical management, particularly for recurrent disease. As the urinary system is a major clearance route of circulating extracellular vesicles (EVs; 30–1000 nm nanoparticles) we explored whether sampling urinary-EVs could serve...
Article
Background and purpose: IDH-mutant gliomas are further divided on the basis of 1p/19q status: oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and astrocytoma, IDH-mutant (without codeletion). Occasionally, testing may reveal single-arm 1p or 19q deletion (unideletion), which remains within the diagnosis of astrocytoma. Molecular assessment has...
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We report the first case of CTE in a former professional female footballer.
Article
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Purpose: The increasing importance of molecular markers for classification and prognostication of diffuse gliomas has prompted the use of imaging features to predict genotype ("radiogenomics"). CDKN2A/B homozygous deletion has only recently been added to the diagnostic paradigm for IDH[isocitrate dehydrogenase]-mutant astrocytomas; thus, associate...
Article
Full-text available
Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition, in which the only known cause is exposure to repeated episodes of blunt head trauma. It most often occurs in professional and amateur athletes who have had frequent and repetitive cranial impacts during contact sports, but may also be found in victims of domestic violence, mil...
Article
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Simple Summary Glioblastoma is a complex and aggressive primary brain tumour that is rapidly fatal. Timely and accurate diagnosis is therefore crucial. Here, we explore the newly emerging field of epitranscriptomics to understand the modifications that occur on RNA molecules in the healthy and diseased brain, focusing on glioblastoma. RNA modificat...
Article
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Potentially toxic elements such as lead and aluminium have been proposed to play a role in the pathogenesis of multiple sclerosis (MS), since their neurotoxic mechanisms mimic many of the pathogenetic processes in MS. We therefore examined the distribution of several potentially toxic elements in the autopsied brains of people with and without MS,...
Article
BACKGROUND VERTU was a randomized phase II trial evaluating veliparib, a brain-penetrant PARP inhibitor, combined with radiotherapy and temozolomide, for patients with newly diagnosed MGMT-unmethylated glioblastoma. As part of planned correlative work after study completion, we assessed genome-wide DNA methylation patterns to predict methylation cl...
Article
BACKGROUND IDH-mutant astrocytomas with CDKN2A/B homozygous deletions (HD) are now categorized as grade 4 astrocytomas. It is unclear how these HD astrocytomas should be treated. We aimed to compare 3-year outcomes for HD versus heterozygous deleted (HeD) IDH-mutant astrocytomas, describe the prognostic impact of deletions relative to histologic gr...
Article
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Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient...
Article
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Extracellular vesicles (EVs) are lipid-membrane enclosed nanoparticles that play significant roles in health and disease. EVs are abundant in body fluids and carry an array of molecules (proteins, lipids, nucleic acids and glycans) that reflect the identity and activity of their cell-of-origin. While the advent of high throughput omics technologies...
Article
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Chronic traumatic encephalopathy (CTE) is a neuropathological diagnosis defined by a unique pattern of hyperphosphorylated tau (p-tau) accumulation that begins in neocortical regions of the brain. It is associated with a range of neuropsychological symptoms, but a definitive diagnosis can only be made by postmortem brain examination. In 2018, we in...
Article
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Millions of individuals are exposed to repetitive head impacts (RHI) each year through contact sports, military blast, and interpersonal violence. RHI is the major risk factor for developing chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. Recent consensus criteria defined the pathognomonic lesion in CTE as perivascular, hyper...
Article
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Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with a history of repetitive head impacts (RHI). CTE was described in boxers as early as the 1920s and by the 1950s it was widely accepted that hits to the head caused some boxers to become “punch drunk.” However, the recent discovery of CTE in American and Australian-...
Article
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Routine examination of entire histological slides at cellular resolution poses a significant if not insurmountable challenge to human observers. However, high-resolution data such as the cellular distribution of proteins in tissues, e.g., those obtained following immunochemical staining, are highly desirable. Our present study extends the applicabi...
Article
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In this Perspective we explore the evolution of our understanding of chronic traumatic encephalopathy (CTE) and its relationship with repetitive head injury. As with many neurodegenerative conditions, there is an imperfect correspondence between neuropathology and clinical phenotype, but unlike other neurodegenerative diseases, CTE has a discrete a...
Article
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Purpose Molecular biomarkers are important for classifying intracranial gliomas, prompting research into correlating imaging with genotype (“radiogenomics”). A limitation of the existing radiogenomics literature is the paucity of studies specifically characterizing grade 2–3 gliomas into the three key molecular subtypes. Our study investigated the...
Article
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RECENT revelations of plagiarism by Australian sports neurologist Dr Paul McCrory () have sent shockwaves through professional sporting bodies internationally. As a leading member of the international Concussion in Sport Group (CISG) for over 20 years, Dr McCrory’s downfall has cast doubt over international consensus guidelines for the management o...
Article
Full-text available
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy caused by repetitive head injury. Although it has chiefly been studied in contact sport participants, anyone who experiences repetitive head injury is at risk of CTE. It is associated with a range of neuro-psychological problems, ranging from mood and behavioural symptoms to co...
Article
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Introduction Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. L...
Article
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BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporane...
Article
Introduction: Creutzfeldt-Jakob disease (CJD), a spongiform encephalopathy, caused by a transmissible misfolded cellular prion protein, is a rapidly progressive, debilitating neurodegenerative disorder with no effective treatment. The estimated global incidence is at 1/million inhabitants. This retrospective study examined the incidence of CJD in...
Article
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Five international consensus statements on concussion in sports have been published. This commentary argues that there is a strong need for a new approach to them that foregrounds public health expertise and patient-centered guidance. Doing so will help players, parents and practitioners keep perspective about these potentially life-altering injuri...
Article
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Introduction: This paper describes a case of bi-frontal vasogenic oedema associated with bilateral frontal lobe and left parietal lobe white matter lesions where extensive investigations, including brain biopsy, failed to establish a diagnosis. Case report: A 67-year-old female presented with three weeks' history of memory loss, fatigue, insomni...
Conference Paper
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Introduction We describe an atypical case of fulminant acute disseminated encephalomyelitis (ADEM). Case A 47 year-old Southeast Asian lady presented after developing headache, aphasia and right hemiparesis over four hours, preceded by dry cough for one week and fevers for two days. CT brain noted vasogenic oedema without enhancement in the left f...
Article
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CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an extremely rare neurologic inflammatory condition. Fewer than 10 pediatric cases have been described. Debate persists as to whether it is a distinct disease or a clinical, radiologic, and histologic phenotype evolving into another disorder....
Article
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Background Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O 6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly ADP-ribose polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide...
Article
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Aim: This study investigated the somatosensory and corticomotor physiology of retired contact sport athletes with a history of repeated concussion/subconcussion head trauma. Methods: Retired male athletes with a history of playing contact sports and repeated head trauma (n = 122) were divided into two groups: those who expressed concerns regarding...
Article
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We have developed a platform, termed PathoFusion, which is an integrated system for marking, training, and recognition of pathological features in whole-slide tissue sections. The platform uses a bifocal convolutional neural network (BCNN) which is designed to simultaneously capture both index and contextual feature information from shorter and lon...
Article
BACKGROUND Histone mutations in the K27M gene were first described in 2014, and incorporated into the WHO CNS tumour classification system in 2016. They are typically associated with diffuse midline gliomas (DMG). Presenting symptoms vary greatly, with some experiencing significant delay in diagnosis. Median survival is only 9-12 months for these p...
Chapter
This chapter will overview the functional injury definition of concussion, then discuss the pathophysiology of concussion leading into the advantages and disadvantages of the electrophysiological methods presented in this chapter, and key variables measured in concussion/mTBI research.
Article
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Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, pro...
Article
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Extracellular vesicles (EVs) play key roles in glioblastoma (GBM; astrocytoma grade IV) biology and are novel sources of biomarkers. EVs released from GBM tumors can cross the blood-brain-barrier into the periphery carrying GBM molecules, including small non-coding RNA (sncRNA). Biomarkers cargoed in circulating EVs have shown great promise for ass...
Article
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Improving outcomes for diffuse glioma patients requires methods that can accurately and sensitively monitor tumour activity and treatment response. Extracellular vesicles (EV) are membranous nanoparticles that can traverse the blood–brain-barrier, carrying oncogenic molecules into the circulation. Measuring clinically relevant glioma biomarkers car...
Article
Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now me...
Article
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Objective Damage to locus ceruleus neurons could play a part in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis because of impairment of the blood-brain barrier and enhanced neuroinflammation. The locus ceruleus has connections throughout the brain and spinal cord, so the char...
Article
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MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While TP53 deletion is rare in glioblastomas, these tumors often carry TP53 mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53wt stabiliza...
Preprint
Full-text available
There is a real need for biomarkers that can indicate glioma disease burden and inform clinical management, particularly in the recurrent glioblastoma (GBM; grade IV glioma) setting where treatment-associated brain changes can confound current and expensive tumour surveillance methods. In this regard, extracellular vesicles (EVs; 30-1000 nm membran...
Article
Full-text available
The first case report of chronic traumatic encephalopathy (CTE) in a National Football League player in 2005 opened the floodgates for the identification of CTE in American football. CTE is now reported in ex-players of other contact sports, including ice hockey, soccer, rugby union, and most recently in Australian rugby league. To date, repetitive...
Conference Paper
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The Australian Sports Brain Bank was established in March 2108 with the aim of characterising the spectrum of neurodegenerative disease among ex-players of Australian contact sports. To date, the ASBB has received over 250 pledges and ten post-mortem brain donations. We will present the clinical and pathological findings of our completed brain exam...
Article
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Persistent post concussion symptoms (PPCS) describe the condition when an individual experiences chronic symptoms, particularly fatigue, beyond the expected time of recovery. The aim of this study was to quantify the effect of fatigue and related ongoing symptoms on somatosensory and corticomotor pathways using reaction time (RT) testing, and singl...
Article
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We and others have previously demonstrated the potential for circulating exosome microRNAs to aid in disease diagnosis. In this study, we sought the possible utility of serum exosome microRNAs as biomarkers for disease activity in multiple sclerosis patients in response to fingolimod therapy. We studied patients with relapsing-remitting multiple sc...
Conference Paper
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Background and Aims: The Australian Sports Brain Bank launched in March 2018, as a collaboration between the Neuropathology Department of RPA Hospital and the Brain & Mind Centre, University of Sydney. The aim of the ASBB is to describe the spectrum of neurodegenerative disease that may be associated with sporting and non-sporting concussion in Aus...
Article
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Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS...
Article
BACKGROUND TMZ offers minimal benefit in pts with de novo uMGMT GBM. V is synergistic with RT and TMZ in uMGMT preclinical GBM models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. VERTU tested V in pts with uMGMT GBM. METHODS VERTU is a randomized Phase 2 trial comparing Standard Arm (Arm A),...
Article
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Varicella-zoster virus (VZV) is a human herpesvirus which causes varicella (chicken pox) during primary infection, establishes latency in sensory ganglia, and can reactivate from this site to cause herpes zoster (HZ) (shingles). A major complication of HZ is a severe and often debilitating pain called post-herpetic neuralgia (PHN) which persists lo...
Article
Background A key component of cancer research is the availability of clinical samples with appropriately annotated clinical data. Biobanks facilitate research by collecting/storing various types of clinical samples for research. Brain Cancer Biobanking Australia (BCBA) was established to facilitate the networking of brain cancer biobanking operatio...
Article
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In the original publication of this article [1] the term ‘National Rugby League (NRL)’ was used to refer to professional rugby league competition sport in Australia. The term should have read ‘professional rugby league’ to include the various professional competition nomenclatures over the last fifty years, including but not limited to NRL. In this...
Article
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The role of astrocytes is becoming increasingly important to understanding how glioblastoma (GBM) tumor cells diffusely invade the brain. Yet, little is known of the contribution of extracellular vesicle (EV) signaling in GBM/astrocyte interactions. We modeled GBM-EV signaling to normal astrocytes in vitro to assess whether this mode of intercellul...
Article
2011 Background: TMZ offers minimal benefit in uMGMT GBM pts. V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. This study examined a novel approach to patients with uMGMT GBM. Methods: VERTU is a randomized Phase 2 trial comparing Arm A...
Article
Diffuse gliomas (grades II–IV) are amongst the most frequent and devastating primary brain tumours of adults. Currently, patients are monitored by clinical examination and radiographic imaging, which can be challenging to interpret and insensitive to early signs of treatment failure and tumour relapse. While brain biopsy and histologic analysis can...
Article
Leptomeningitis is a rare central nervous system manifestation of rheumatoid arthritis, generally in patients with established chronic rheumatoid disease. We report a 41-year-old man without previous rheumatoid arthritis or psychiatric disorder who presented with an acute neuropsychiatric disturbance and polyarthralgia. His MR scan of brain showed...
Article
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Exosomes are nano-sized extracellular vesicles released by many cells that contain molecules characteristic of their cell of origin, including microRNA. Exosomes released by glioblastoma cross the blood–brain barrier into the peripheral circulation and carry molecular cargo distinct to that of “free-circulating” miRNA. In this pilot study, serum ex...