Alastair Corbett | The University of Sydney (original) (raw)

Papers by Alastair Corbett

Seminars in Neurology, 1983

Neurology, 1982

ALS and chronic spinal muscular atrophy are characterized by wasting of skeletal muscle, suggesti... more ALS and chronic spinal muscular atrophy are characterized by wasting of skeletal muscle, suggesting accelerated catabolism or reduced synthesis of muscle protein. We studied seven patients with ALS and three with chronic spinal muscular atrophy using 24-hour urinary 3-methylhistidine excretion as a measure of the rate of muscle catabolism and 24-hour urinary creatinine excretion as an index of significantly and similarly higher in both groups of patients than in controls (p less than 0.0005), implying a state of accelerated skeletal muscle protein catabolism in these diseases.

Journal of Neuromuscular Diseases, 2016

Clinical Science, Nov 1, 1986

To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and t... more To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and to determine if these same patients display signs of a whole body decrease in the action of insulin on amino acid uptake and glucose disposal, three separate 120 min studies employing the euglycaemic insulin clamp technique (20, 80 and 200 m-units min-1 m-2) were performed on five ambulatory patients with myotonic dystrophy. The results were compared with findings obtained in identical studies in 21 normal volunteers. Myotonic dystrophy patients showed a slower, less marked decline in the serum concentration of insulin sensitive amino acids (threonine, valine, leucine, isoleucine, tyrosine, phenylalanine) during all three insulin infusions compared with normals. The greatest difference occurred at the low physiological elevations of insulin produced by the 20 m-units min-1 m-2 infusion. Alanine levels fell significantly below baseline in patients with myotonic dystrophy after 60 and 120 min of insulin infusion with all three rates of insulin infusion. Normal subjects had only a minimal, insignificant decline in arterialized alanine concentrations during the three different insulin infusions. Creatinine adjusted rates of whole body glucose disposal were 30-40% lower in the myotonic dystrophy group at all three doses of insulin compared with the normals. This demonstrates that their insulin resistance was not due simply to a reduction in muscle mass. The overall pattern of findings in these studies of patients with myotonic dystrophy indicates that there is a whole body derangement in the regulation of circulating amino acid levels by insulin as well as a marked decrease in the action of this hormone in stimulating glucose uptake by target tissues.

JAMA neurology, Jan 5, 2015

To our knowledge, the efficacy of transferring next-generation sequencing from a research setting... more To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated. To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic change...

Brain : a journal of neurology, Jan 12, 2015

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum rangi... more Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis.

Neuromuscular Disorders, 2008

Previous studies have differed as to whether APOE e4 is a susceptibility factor for developing sp... more Previous studies have differed as to whether APOE e4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the e2 allele.

Stroke, 2003

Background and Purpose-Stroke represents the third-leading cause of death in Western society. Pro... more Background and Purpose-Stroke represents the third-leading cause of death in Western society. Prompt and appropriate intervention for those with stroke or at risk of stroke is highly dependent on general practitioners' (GPs') knowledge and referral practices. Methods-We randomly selected 490 eligible GPs from New South Wales, Australia, to complete our self-administered questionnaire. Case scenarios were used to assess GPs' knowledge of transient ischemic attack/ stroke risk factors, stroke prevention strategies, and management of asymptomatic and symptomatic patients. Results-We received 296 completed questionnaires (60% response rate). Nearly all GPs (286, 96.6%) strongly agreed or agreed that stroke is a medical emergency. Most were aware that management by multidisciplinary teams improves outcomes (strongly agree or agree, 279; 94.3%). GPs endorsed the effectiveness of aspirin and warfarin in reducing stroke morbidity. GPs also were aware of the benefit of carotid endarterectomy (CEA) for symptomatic patients with Ͼ80% carotid stenosis but were less aware of the value of CEA for symptomatic patients with moderate stenosis. Vascular surgeon was the specialist of choice for referral of patients with high-grade carotid stenosis. Few GPs reported having seen the Cochrane Collaboration reviews of CEA for symptomatic (3.0%) and asymptomatic (1.7%) patients. Conclusions-GPs were well apprised of the evidence to support CEA for symptomatic patients with high-grade carotid stenosis. Our findings, however, invite more purposeful and effective education of GPs about stroke prevention, diagnosis, and management if optimal outcomes are to be realized. (Stroke. 2003;34:2681-2686.)

Respiratory Physiology & Neurobiology, 2011

There has been increasing recognition of pre-motor manifestations of Parkinson&am... more There has been increasing recognition of pre-motor manifestations of Parkinson's disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO(2). Arterial blood gases were taken at rest and following 20 min exposure to 15% O(2). A linear correlation assessed associations between respiratory function and indices of PD severity. 19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function. Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows.

Neuroradiology, 1995

We describe a 44-year-old woman with progressive cervical pain in whom plain films of the cervica... more We describe a 44-year-old woman with progressive cervical pain in whom plain films of the cervical spine showed only minor syndesmophyte formation when the patient first presented. However, after 5 weeks, repeat films demonstrated heavy symmetrical calcification of the cervical dorsal root ganglia. A review of the literature did not reveal a previous description of these findings.

Neuromuscular Disorders, 2007

IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway... more IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway (UPP). Mutations in VCP may affect this pathway. We explored the mechanism by which VCP leads to IBM using patient tissue, cell culture and a transgenic animal. Histochemical examination of 9 IBMPFD patient muscle biopsies (4 families; 2 mutations) reveals that 7/9 contained rimmed vacuoles while all had evidence of ubiquitinated and VCP inclusions. These inclusions were myonuclear and sarcoplasmic in location. We generated tetracycline inducible cell lines that express VCP-WT, dominant negative VCP or several IBMPFD mutant VCP proteins. These cells express exogenous VCP at 1-2 times the level of endogenous VCP. Remarkably, IBMPFD mutant VCP expressing cells have a dramatic increase in ubiquitinated proteins as measured by immunofluorescence and Western blot. This finding is similar to the expression of a dominant negative VCP protein. IBMPFD mutant expressing cells fail to degrade a UPP reporter and are more sensitive to proteasome inhibition as measured by cell death assays. Transgenic expression of IBMPFD mutant VCP R155H in the skeletal muscle of mice results in animal weakness that begins at 6 months of age. Consistent with our patient and cell culture data, these animals have an increase in ubiquitinated protein inclusions as compared with VCP-WT control animals. The increase in ubiquitinated proteins may be due to a reduction in the activity of the 20S proteasome in these animals. We suggest that IBMPFD mutations in VCP lead to a perturbation in the UPP resulting in the accumulation of undegraded ubiquitinated proteins, myopathic changes and muscle weakness. This study lends insight into the pathogenesis of IBMPFD as well as other hIBMs and the more common sporadic IBM.

Neuromuscular Disorders, 2007

IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway... more IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway (UPP). Mutations in VCP may affect this pathway. We explored the mechanism by which VCP leads to IBM using patient tissue, cell culture and a transgenic animal. Histochemical examination of 9 IBMPFD patient muscle biopsies (4 families; 2 mutations) reveals that 7/9 contained rimmed vacuoles while all had evidence of ubiquitinated and VCP inclusions. These inclusions were myonuclear and sarcoplasmic in location. We generated tetracycline inducible cell lines that express VCP-WT, dominant negative VCP or several IBMPFD mutant VCP proteins. These cells express exogenous VCP at 1-2 times the level of endogenous VCP. Remarkably, IBMPFD mutant VCP expressing cells have a dramatic increase in ubiquitinated proteins as measured by immunofluorescence and Western blot. This finding is similar to the expression of a dominant negative VCP protein. IBMPFD mutant expressing cells fail to degrade a UPP reporter and are more sensitive to proteasome inhibition as measured by cell death assays. Transgenic expression of IBMPFD mutant VCP R155H in the skeletal muscle of mice results in animal weakness that begins at 6 months of age. Consistent with our patient and cell culture data, these animals have an increase in ubiquitinated protein inclusions as compared with VCP-WT control animals. The increase in ubiquitinated proteins may be due to a reduction in the activity of the 20S proteasome in these animals. We suggest that IBMPFD mutations in VCP lead to a perturbation in the UPP resulting in the accumulation of undegraded ubiquitinated proteins, myopathic changes and muscle weakness. This study lends insight into the pathogenesis of IBMPFD as well as other hIBMs and the more common sporadic IBM.

Neuromuscular Disorders, 2009

Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestr... more Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM.

Journal of the American Geriatrics Society, 2002

To identify predictors of activity of daily living (ADL) and instrumental activity of daily livin... more To identify predictors of activity of daily living (ADL) and instrumental activity of daily living (IADL) decline in a population with subcortical vascular dementia (SVD) and to evaluate potential mechanism of decline. DESIGN: Longitudinal. SETTING: Hospital-based. PARTICIPANTS: Computed tomographic (CT) scanning identified 77 participants as having subcortical infarction. MEASUREMENTS: Participants were neurologically, neuropsychologically, behaviorally, and functionally assessed four times over 5.82 years. Baseline data were grouped into four modules: basic demographic and risk factor, CT scan, neurological and other clinical, and neuropsychological and behavioral. Multivariate analysis determined predictors of decline in ADLs and IADLs. RESULTS: Predictors of ADL decline were age, alcohol consumption, coordination, snout reflex, and performance on a neuropsychological test (Block Design). Predictors of IADL decline were predominantly cognitive and included the presence of paratonia and performance on the two neuropsychological tests (attention and memory tasks). CONCLUSION: These findings suggest that cognitive impairments are most likely to have an effect on IADL function, because the skills involved are complex and involve integrative activity, whereas physical and cognitive impairments combined are likely to compromise ADL function, given the more basic and physical nature of the functions involved. These findings indicate that in people with SVD, both ADL and IADL status should be moni-tored, because, for many, decline in function over time is likely, and thus the provision of appropriate support required.

Journal of Neurology, Neurosurgery & Psychiatry, 2008

There have been few studies of the variability in the clinical phenotype in sporadic inclusion bo... more There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.

Journal of Clinical Neuroscience, 2004

Our patient suffered from severe and prolonged dysphagia following an apparently uncomplicated th... more Our patient suffered from severe and prolonged dysphagia following an apparently uncomplicated three-level cervical corpectomy with iliac crest graft and anterior cervical plate fusion. Multi-level anterior cervical surgery forms a routine part of the regular spinal practice of the senior author (G.W.). Despite this, this complication has not previously been observed. A clear cause has not been identified in this patient. We speculate that the complication resulted from a combination of excessive oesophageal retraction and post-operative subcutaneous oedema. However, whether mechanical retraction disrupts the neural supply of the oesophagus or induces a state of dysmotility is not known and is a subject for further research. The surgical approach for multilevel cervical corpectomies requires a generous exposure obtained by meticulous dissection of tissue planes. The complication may be further minimized by cautious placement of retractor blades under the longus colli muscles during retraction. In this patient, we further speculate that his severe pre-morbid myelopathic state may also be a significant contributing factor.

Journal of Clinical Neuroscience, 2004

We report the case of a 72-year-old man with a history of Parkinson&a... more We report the case of a 72-year-old man with a history of Parkinson's Disease who presented with a history of falls, cognitive impairment and depressed mood. Neurological examination revealed moderate rigidity and bradykinesia. Alterations to his anti-Parkinsonian medication resulted in improvements in his mobility but no change in mental state. He was also noted to have developed multiple raised skin lesions. One of these lesions was biopsied and grew Cryptococcus neoformans. He subsequently had a cerebral MRI scan which showed enhancing lesions, in the left parietal lobe and right superior cerebellar peduncle, consistent with intracranial cryptococcal infection. Images of one of the skin lesions and the cerebral MRI scan are shown.

Journal of Clinical Neuroscience, 2008

The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations an... more The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community.

Journal of the American Geriatrics Society, 2006

To identify the clinical correlates of functional incapacity in the community living "old-ol... more To identify the clinical correlates of functional incapacity in the community living "old-old."

European Archives of Psychiatry and Clinical Neuroscience, 2006

j Abstract Gait disturbance and cognitive changes are common with ageing. The cerebellum contribu... more j Abstract Gait disturbance and cognitive changes are common with ageing. The cerebellum contributes to motor coordination and participates in various aspects of cognition. However, no research has investigated the possible cerebellar contribution to gait and cognition in non-demented very old individuals. The current study aimed to determine the associations between indices of cerebellar size (vermal area and total volume) and measures of motor and cognitive integrity, as well as the role of variables known to impact on cerebellar size (alcohol consumption and chronological age) in a sample of 111 community dwellers (mean age: 85 years; range: 81-97 years). A marginally significant association was present between age and total vermal area. Significant correlations between current daily alcohol intake and some vermal areas were observed. These associations were more pronounced in men, particularly after controlling for cerebrum size. Multiple linear regression models revealed limited unique contributions of cerebellar predictors to neurological and cognitive measures. In summary, the results indicate that the cerebellum may be susceptible to alcohol-related shrinkage in non-demented very old individuals, more so in men, even at low dose. It also appears that the observed changes in cerebellum size in this population contribute little to neurological and cognitive changes. j

Seminars in Neurology, 1983

Neurology, 1982

ALS and chronic spinal muscular atrophy are characterized by wasting of skeletal muscle, suggesti... more ALS and chronic spinal muscular atrophy are characterized by wasting of skeletal muscle, suggesting accelerated catabolism or reduced synthesis of muscle protein. We studied seven patients with ALS and three with chronic spinal muscular atrophy using 24-hour urinary 3-methylhistidine excretion as a measure of the rate of muscle catabolism and 24-hour urinary creatinine excretion as an index of significantly and similarly higher in both groups of patients than in controls (p less than 0.0005), implying a state of accelerated skeletal muscle protein catabolism in these diseases.

Journal of Neuromuscular Diseases, 2016

Clinical Science, Nov 1, 1986

To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and t... more To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and to determine if these same patients display signs of a whole body decrease in the action of insulin on amino acid uptake and glucose disposal, three separate 120 min studies employing the euglycaemic insulin clamp technique (20, 80 and 200 m-units min-1 m-2) were performed on five ambulatory patients with myotonic dystrophy. The results were compared with findings obtained in identical studies in 21 normal volunteers. Myotonic dystrophy patients showed a slower, less marked decline in the serum concentration of insulin sensitive amino acids (threonine, valine, leucine, isoleucine, tyrosine, phenylalanine) during all three insulin infusions compared with normals. The greatest difference occurred at the low physiological elevations of insulin produced by the 20 m-units min-1 m-2 infusion. Alanine levels fell significantly below baseline in patients with myotonic dystrophy after 60 and 120 min of insulin infusion with all three rates of insulin infusion. Normal subjects had only a minimal, insignificant decline in arterialized alanine concentrations during the three different insulin infusions. Creatinine adjusted rates of whole body glucose disposal were 30-40% lower in the myotonic dystrophy group at all three doses of insulin compared with the normals. This demonstrates that their insulin resistance was not due simply to a reduction in muscle mass. The overall pattern of findings in these studies of patients with myotonic dystrophy indicates that there is a whole body derangement in the regulation of circulating amino acid levels by insulin as well as a marked decrease in the action of this hormone in stimulating glucose uptake by target tissues.

JAMA neurology, Jan 5, 2015

To our knowledge, the efficacy of transferring next-generation sequencing from a research setting... more To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated. To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic change...

Brain : a journal of neurology, Jan 12, 2015

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum rangi... more Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis.

Neuromuscular Disorders, 2008

Previous studies have differed as to whether APOE e4 is a susceptibility factor for developing sp... more Previous studies have differed as to whether APOE e4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the e2 allele.

Stroke, 2003

Background and Purpose-Stroke represents the third-leading cause of death in Western society. Pro... more Background and Purpose-Stroke represents the third-leading cause of death in Western society. Prompt and appropriate intervention for those with stroke or at risk of stroke is highly dependent on general practitioners' (GPs') knowledge and referral practices. Methods-We randomly selected 490 eligible GPs from New South Wales, Australia, to complete our self-administered questionnaire. Case scenarios were used to assess GPs' knowledge of transient ischemic attack/ stroke risk factors, stroke prevention strategies, and management of asymptomatic and symptomatic patients. Results-We received 296 completed questionnaires (60% response rate). Nearly all GPs (286, 96.6%) strongly agreed or agreed that stroke is a medical emergency. Most were aware that management by multidisciplinary teams improves outcomes (strongly agree or agree, 279; 94.3%). GPs endorsed the effectiveness of aspirin and warfarin in reducing stroke morbidity. GPs also were aware of the benefit of carotid endarterectomy (CEA) for symptomatic patients with Ͼ80% carotid stenosis but were less aware of the value of CEA for symptomatic patients with moderate stenosis. Vascular surgeon was the specialist of choice for referral of patients with high-grade carotid stenosis. Few GPs reported having seen the Cochrane Collaboration reviews of CEA for symptomatic (3.0%) and asymptomatic (1.7%) patients. Conclusions-GPs were well apprised of the evidence to support CEA for symptomatic patients with high-grade carotid stenosis. Our findings, however, invite more purposeful and effective education of GPs about stroke prevention, diagnosis, and management if optimal outcomes are to be realized. (Stroke. 2003;34:2681-2686.)

Respiratory Physiology & Neurobiology, 2011

There has been increasing recognition of pre-motor manifestations of Parkinson&am... more There has been increasing recognition of pre-motor manifestations of Parkinson's disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO(2). Arterial blood gases were taken at rest and following 20 min exposure to 15% O(2). A linear correlation assessed associations between respiratory function and indices of PD severity. 19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function. Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows.

Neuroradiology, 1995

We describe a 44-year-old woman with progressive cervical pain in whom plain films of the cervica... more We describe a 44-year-old woman with progressive cervical pain in whom plain films of the cervical spine showed only minor syndesmophyte formation when the patient first presented. However, after 5 weeks, repeat films demonstrated heavy symmetrical calcification of the cervical dorsal root ganglia. A review of the literature did not reveal a previous description of these findings.

Neuromuscular Disorders, 2007

IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway... more IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway (UPP). Mutations in VCP may affect this pathway. We explored the mechanism by which VCP leads to IBM using patient tissue, cell culture and a transgenic animal. Histochemical examination of 9 IBMPFD patient muscle biopsies (4 families; 2 mutations) reveals that 7/9 contained rimmed vacuoles while all had evidence of ubiquitinated and VCP inclusions. These inclusions were myonuclear and sarcoplasmic in location. We generated tetracycline inducible cell lines that express VCP-WT, dominant negative VCP or several IBMPFD mutant VCP proteins. These cells express exogenous VCP at 1-2 times the level of endogenous VCP. Remarkably, IBMPFD mutant VCP expressing cells have a dramatic increase in ubiquitinated proteins as measured by immunofluorescence and Western blot. This finding is similar to the expression of a dominant negative VCP protein. IBMPFD mutant expressing cells fail to degrade a UPP reporter and are more sensitive to proteasome inhibition as measured by cell death assays. Transgenic expression of IBMPFD mutant VCP R155H in the skeletal muscle of mice results in animal weakness that begins at 6 months of age. Consistent with our patient and cell culture data, these animals have an increase in ubiquitinated protein inclusions as compared with VCP-WT control animals. The increase in ubiquitinated proteins may be due to a reduction in the activity of the 20S proteasome in these animals. We suggest that IBMPFD mutations in VCP lead to a perturbation in the UPP resulting in the accumulation of undegraded ubiquitinated proteins, myopathic changes and muscle weakness. This study lends insight into the pathogenesis of IBMPFD as well as other hIBMs and the more common sporadic IBM.

Neuromuscular Disorders, 2007

IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway... more IBMPFD). VCP is involved in many cellular pathways; most notably the ubiquitin proteasome pathway (UPP). Mutations in VCP may affect this pathway. We explored the mechanism by which VCP leads to IBM using patient tissue, cell culture and a transgenic animal. Histochemical examination of 9 IBMPFD patient muscle biopsies (4 families; 2 mutations) reveals that 7/9 contained rimmed vacuoles while all had evidence of ubiquitinated and VCP inclusions. These inclusions were myonuclear and sarcoplasmic in location. We generated tetracycline inducible cell lines that express VCP-WT, dominant negative VCP or several IBMPFD mutant VCP proteins. These cells express exogenous VCP at 1-2 times the level of endogenous VCP. Remarkably, IBMPFD mutant VCP expressing cells have a dramatic increase in ubiquitinated proteins as measured by immunofluorescence and Western blot. This finding is similar to the expression of a dominant negative VCP protein. IBMPFD mutant expressing cells fail to degrade a UPP reporter and are more sensitive to proteasome inhibition as measured by cell death assays. Transgenic expression of IBMPFD mutant VCP R155H in the skeletal muscle of mice results in animal weakness that begins at 6 months of age. Consistent with our patient and cell culture data, these animals have an increase in ubiquitinated protein inclusions as compared with VCP-WT control animals. The increase in ubiquitinated proteins may be due to a reduction in the activity of the 20S proteasome in these animals. We suggest that IBMPFD mutations in VCP lead to a perturbation in the UPP resulting in the accumulation of undegraded ubiquitinated proteins, myopathic changes and muscle weakness. This study lends insight into the pathogenesis of IBMPFD as well as other hIBMs and the more common sporadic IBM.

Neuromuscular Disorders, 2009

Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestr... more Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM.

Journal of the American Geriatrics Society, 2002

To identify predictors of activity of daily living (ADL) and instrumental activity of daily livin... more To identify predictors of activity of daily living (ADL) and instrumental activity of daily living (IADL) decline in a population with subcortical vascular dementia (SVD) and to evaluate potential mechanism of decline. DESIGN: Longitudinal. SETTING: Hospital-based. PARTICIPANTS: Computed tomographic (CT) scanning identified 77 participants as having subcortical infarction. MEASUREMENTS: Participants were neurologically, neuropsychologically, behaviorally, and functionally assessed four times over 5.82 years. Baseline data were grouped into four modules: basic demographic and risk factor, CT scan, neurological and other clinical, and neuropsychological and behavioral. Multivariate analysis determined predictors of decline in ADLs and IADLs. RESULTS: Predictors of ADL decline were age, alcohol consumption, coordination, snout reflex, and performance on a neuropsychological test (Block Design). Predictors of IADL decline were predominantly cognitive and included the presence of paratonia and performance on the two neuropsychological tests (attention and memory tasks). CONCLUSION: These findings suggest that cognitive impairments are most likely to have an effect on IADL function, because the skills involved are complex and involve integrative activity, whereas physical and cognitive impairments combined are likely to compromise ADL function, given the more basic and physical nature of the functions involved. These findings indicate that in people with SVD, both ADL and IADL status should be moni-tored, because, for many, decline in function over time is likely, and thus the provision of appropriate support required.

Journal of Neurology, Neurosurgery & Psychiatry, 2008

There have been few studies of the variability in the clinical phenotype in sporadic inclusion bo... more There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.

Journal of Clinical Neuroscience, 2004

Our patient suffered from severe and prolonged dysphagia following an apparently uncomplicated th... more Our patient suffered from severe and prolonged dysphagia following an apparently uncomplicated three-level cervical corpectomy with iliac crest graft and anterior cervical plate fusion. Multi-level anterior cervical surgery forms a routine part of the regular spinal practice of the senior author (G.W.). Despite this, this complication has not previously been observed. A clear cause has not been identified in this patient. We speculate that the complication resulted from a combination of excessive oesophageal retraction and post-operative subcutaneous oedema. However, whether mechanical retraction disrupts the neural supply of the oesophagus or induces a state of dysmotility is not known and is a subject for further research. The surgical approach for multilevel cervical corpectomies requires a generous exposure obtained by meticulous dissection of tissue planes. The complication may be further minimized by cautious placement of retractor blades under the longus colli muscles during retraction. In this patient, we further speculate that his severe pre-morbid myelopathic state may also be a significant contributing factor.

Journal of Clinical Neuroscience, 2004

We report the case of a 72-year-old man with a history of Parkinson&a... more We report the case of a 72-year-old man with a history of Parkinson's Disease who presented with a history of falls, cognitive impairment and depressed mood. Neurological examination revealed moderate rigidity and bradykinesia. Alterations to his anti-Parkinsonian medication resulted in improvements in his mobility but no change in mental state. He was also noted to have developed multiple raised skin lesions. One of these lesions was biopsied and grew Cryptococcus neoformans. He subsequently had a cerebral MRI scan which showed enhancing lesions, in the left parietal lobe and right superior cerebellar peduncle, consistent with intracranial cryptococcal infection. Images of one of the skin lesions and the cerebral MRI scan are shown.

Journal of Clinical Neuroscience, 2008

The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations an... more The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community.

Journal of the American Geriatrics Society, 2006

To identify the clinical correlates of functional incapacity in the community living "old-ol... more To identify the clinical correlates of functional incapacity in the community living "old-old."

European Archives of Psychiatry and Clinical Neuroscience, 2006

j Abstract Gait disturbance and cognitive changes are common with ageing. The cerebellum contribu... more j Abstract Gait disturbance and cognitive changes are common with ageing. The cerebellum contributes to motor coordination and participates in various aspects of cognition. However, no research has investigated the possible cerebellar contribution to gait and cognition in non-demented very old individuals. The current study aimed to determine the associations between indices of cerebellar size (vermal area and total volume) and measures of motor and cognitive integrity, as well as the role of variables known to impact on cerebellar size (alcohol consumption and chronological age) in a sample of 111 community dwellers (mean age: 85 years; range: 81-97 years). A marginally significant association was present between age and total vermal area. Significant correlations between current daily alcohol intake and some vermal areas were observed. These associations were more pronounced in men, particularly after controlling for cerebrum size. Multiple linear regression models revealed limited unique contributions of cerebellar predictors to neurological and cognitive measures. In summary, the results indicate that the cerebellum may be susceptible to alcohol-related shrinkage in non-demented very old individuals, more so in men, even at low dose. It also appears that the observed changes in cerebellum size in this population contribute little to neurological and cognitive changes. j