I believe the Aussies are putting diagnostic and care protocols in place in preparation for a revolution in the treatment of dementia and other debilitating diseases that can be treated by 2-73.
I believe they have sufficent proof that 2-73 works in hand and will approve the drug provisionally when they are prepared to handle the demand for the drug and implement new care protocols.
To approve the drug without this infrastructure would be cruel. The research and agendas presented at the following forum support this belief.
AUSTRALIAN DEMENTIA FORUM Abstracts Accelerating research. Enhancing collaboration. Creating change. Hotel Grand Chancellor Hobart, 13-14 June 2019 abstracts published
Please read the complete document, the following seem most pertinent to my argument::
INTRODUCTION At present, it is estimated that over 436,000 Australians are living with dementia. Globally, a person is diagnosed with dementia every three seconds. Since 2015, the NHMRC National Institute for Dementia Research (NNIDR) has been targeting, coordinating and translating the strategic expansion of dementia research in Australia. By collaborating with researchers; engaging those living with dementia in research efforts and connecting with health Professionals and policy makers, NNIDR is committed to achieving the World Dementia Council’s international target – the identification of a disease-modifying therapy by 2025. It is in this context that we present to you the full program and abstracts of the Australian Dementia Forum 2019: Shining a light on the impact of dementia research (ADF2019). ADF2019 is being held in Hobart on 13-14 June. Building on the success of the Australian Dementia Forum 2018, ADF2019 will bring over 400 leading researchers, health service professionals, policy makers, people living with dementia, their carers and family members, together to examine the enormous impact dementia research has on the Australian community. Researchers submitted over 266 abstracts and of these 73 were selected for presentation, with a further 145 poster presentations across two poster sessions. For the first time in Australian Dementia Forum history, ADF2019 will feature three parallel sessions. Three international keynote speakers will participate in ADF2019, with a further keynote address to be delivered by Australian researcher, Professor Lizzie Coulson. Our international keynotes, Professor Carol Brayne CBE from Cambridge University (United Kingdom), Dr Jeff Williamson from Wake Forest Baptist Health (United States) and Dr Margaret Dudley from the University of Auckland (New Zealand) will each share their insights across prevention, care and living with dementia. ADF2019 will also facilitate vital discussions on dementia research through roundtables, networking opportunities and a research development workshop.
DR CLAIRE BURLEY Dementia Centre for Research Collaboration (DCRC), University of New South Wales, Sydney Preventing and managing the behaviours and psychological symptoms of dementia (BPSD) Behaviours and psychological symptoms of dementia (BPSD) are estimated to effect up to 90 percent of patients and strongly correlate with functional and cognitive impairment (Cerejeira et al., 2012). The topic of BPSD has stirred up much controversy and debate, including: choice of terminology, creating and sustaining dementia friendly communities, reducing stigma through increased education and awareness, determining optimal approaches in the prevention and management, implementing optimal and evidence-based programs through effective knowledge translation, and more recently, determining the economic and societal costs of BPSD on an incremental symptomatic level.
ASSOCIATE PROFESSOR KATE HOY Monash University Stimulating Connections: Advancing Brain Stimulation Research in dementia Dr Ashleigh Smith, NHMRC-ARC Dementia Research Development Fellow, University of South Australia; and Dr Mitchell Goldsworthy, NHMRC-ARC Dementia Research Development Fellow, University of Adelaide Non-invasive brain stimulation techniques hold considerable promise as novel treatment approaches for dementia. In Australia there are currently over 420,000 people suffering from dementia and, with no significant treatment breakthroughs, this number is predicted to rise to over 1.1 million by 2056. Between 2002 and 2012 there were 413 clinical drug trials for Alzheimer’s with an overall failure rate of 99.6%, and of the 244 drugs trialled in this time only one received FDA approval (in 2003). While there are a number of new drugs currently under development, early findings have been largely disappointing. In light of this, the inherent challenges and costs of drug development, and the recent withdrawal of drug companies from Alzheimer’s research (i.e. Pfizer announced in January 2018 that it will be ending its research into drug development for Alzheimer’s) alternative treatment approaches must be considered. Recent findings regarding the pathophysiology of dementia have indeed suggested an alternative treatment approach, with studies showing damage to specific large-scale, distributed, function-critical neural networks. Whereby it may be the pathophysiological consequences (i.e. abnormal neuronal firing patterns) of the relevant neuropathology which are most related to dementia symptoms. Such pathophysiological processes are ideally suited to both investigation and modulation with brain stimulation techniques that can induce both local and global changes in brain activity (i.e., Transcranial Magnetic Stimulation [TMS], Theta Burst Stimulation [TBS], transcranial Direct and Alternating Current Stimulation [tDCS, tACS]). Indeed in the last 24 months there have been a number of highly promising early findings with respect to the therapeutic potential of these techniques
DR EDWIN TAN University of Sydney Safe and effective use of medicines in people living with dementia Edwin Tan 1 , Lisa Kalisch Ellett 2, Tuan Nguyen 2, Julia GilmartinThomas 3, Emily Reeve 2 1 School of Pharmacy, The University of Sydney, Sydney, NSW, Australia, 2 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia, 3 School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia, 4 Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS, Australia Medication use in people with dementia is challenging. People with dementia are often less likely to receive pharmacological treatment and interventional procedures that could enhance quality of life. The evidence for prescribing medications are usually drawn from trials of younger, healthier individuals, and there is limited guidance for prescribing in people with dementia. Pharmacodynamic and pharmacokinetic changes that occur in this vulnerable population increase the risk of toxicity of some medications. Inappropriate medication use can lead to deteriorations in functional capacity and increase the need for hospitalisation and aged care services. In extreme cases, inappropriate medication use may lead to increased morbidity and mortality.
DR LYN PHILLIPSON University of Wollongong Collaborations and priorities for Dementia Friendly Research – A Roundtable Discussion Lyn Phillipson1 and Dennis Frost2 1 University of Wollongong, 2Chair, Southern Dementia Advisory Group (Dementia Friendly Kiama); Member, Dementia Friendly Communities Dementia Advisory Group and Dementia Advisory Committee (Dementia Australia) To address the research priority of ‘living well with dementia’ the Dementia Friendly Communities (DFC) movement has been highlighted as having a role in promoting ‘increased awareness and understanding of rights, needs and experience of people with dementia living in the community’. It may also provide an effective mechanism through which the ‘dignity, independence and self-determination of people with dementia’ can be supported within local communities. However, despite this potential, and the growing number of projects both nationally and internationally, there is currently no strategic or co-ordinated research agenda through which to build an evidence base for these emerging community-based projects. The ‘Dementia Friendly Research Roundtable’ will provide an opportunity for people involved in local ‘Dementia Friendly’ projects to work collaboratively with current and emerging ‘Dementia Friendly’ researchers to: -- Identify research themes and priorities to support building an evidence base for ‘Dementia Friendly’ communities of practice -- Discuss the formation of ongoing Special Interest Groups around these research themes and the resourcing needed to support a DFC ‘Research and Action’ network -- Identify potential opportunities for coordination and collaboration in research around these themes within existing projects -- Identify targets for potential research opportunities and funding
DR CAROL DOBSON-STONE University of Sydney
A novel causative gene for frontotemporal dementia – amyotrophic lateral sclerosis
Additional author credits too huge to post...Note the mention of a “mutant protein”. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically and pathologically overlapping disorders with shared genetic causes. Numerous families exhibiting both disorders have been described, and most of them harbour C9orf72 repeat expansions. However, several C9orf72-negative FTD-ALS families remain and the genetic cause of their disease is unknown. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of FTD-ALS and no mutation in known ALS or dementia genes [Dobson-Stone et al 2013, Acta Neuropathol 125:523-533]. We identified a missense mutation in a gene encoding a lysine-63 deubiquitinase (DUB), within this disease locus. We examined brain tissue of two mutation carriers from this family and observed widespread glial immunoreactivity of the DUB in frontal white matter. The mutant protein showed significantly increased DUB activity, more potent inhibition of the cell signaling molecule NF-kB, and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although mutations in this gene appear to be rare, it interacts with at least three other proteins encoded by FTD/ALS genes, suggesting that this DUB may play a central role in the pathogenesis of these disorders. Our study highlights the importance of autophagy regulation in the pathogenesis of FTD and ALS.
DR DHAMIDHU ERATNE Melbourne Health Neurofilament Light Chain in Neuropsychiatric and Neurodegenerative Disorders: A ‘C-Reactive Protein’ for the Brain?
Additional author credits too huge to post.. . Neurofilament light (NfL) has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of neurological and neurodegenerative disorders. This study explored the utility of cerebrospinal fluid (CSF) NfL in distinguishing primary psychiatric disorders from neurodegenerative and neurological disorders, a common diagnostic dilemma for neurologists and psychiatrists. This cross-sectional retrospective study assessed CSF NfL on patients referred to a tertiary neuropsychiatry service from 2009 to 2017 for diagnostic assessment of neuropsychiatric and neurocognitive symptoms, who received lumbar punctures as part of a comprehensive workup. The most recent gold standard clinical consensus diagnosis was categorised in to psychiatric disorder (PSY) or neurodegenerative or neurological disorder (NND). Data from healthy controls was available for comparison. Data extraction and diagnostic categorisation was blinded to NfL results. 129 participants were included: 77 NND (mean age 57 years), 31 PSY (mean age 51 years), 21 healthy controls (mean age 66 years). NfL was significantly higher in NND (M=3560pg/mL, 95% CIs=[2918, 4601]) compared to PSY (M=949pg/mL, 95% CIs=[830, 1108]) and controls (M=1036pg/mL, 95% CIs=[908, 1165]). NfL distinguished NND from PSY with an area under the curve of 0.94 (95% CIs=[0.89, 0.98]); a cut-off of 1332pg/mL was Associated with 87% sensitivity and 90% specificity. CSF NfL shows promise as a diagnostic test to assist with the often challenging diagnostic dilemma of distinguishing psychiatric disorders from neurodegenerative and neurological disorders. Further studies are warranted to replicate and expand on these findings, including on plasma NfL.
DR FIONA KUMFOR University Of Sydney Delusions in neurodegenerative disorders: insights into the prevalence, nature and neurocognitive mechanisms Additional author credits too huge to post.. . Abnormal beliefs and delusions have been reported in some people with dementia, however, the prevalence of delusions, and their neurocognitive basis has been underexplored. Here, we aimed to examine the prevalence, severity and nature of delusions in a large, diverse cohort of dementia patients. 487 dementia patients were included: 102 Alzheimer’s disease, 136 behavioural-variant frontotemporal dementia (bvFTD), 53 semantic-variant primary progressive aphasia (PPA), 51 nonfluent-variant PPA, 50 logopenic-variant PPA, 29 motor neurone disease, 46 corticobasal syndrome, 20 progressive supranuclear palsy. All patients underwent brain MRI and cognitive assessment, and the Neuropsychiatric Inventory was conducted with an informant. In our cohort, 48/487 patients (10.8%) had delusions, with the highest prevalence observed in behavioural-variant frontotemporal dementia (5%) and Alzheimer’s disease (2.4%). The most common types of delusions were persecutory and delusions of reference. Follow-up analyses revealed that individuals with delusions (n=30) performed worse on the Addenbrooke’s Cognitive Examination (p=.035), particularly the attention (p=.022) and memory (p=.013) subtests, than a demographically-matched group of patients without delusions (n=30). Voxel-based morphometry analyses showed that increased severity of delusions was associated with lower integrity of the cerebellum, posterior cingulate and right superior frontal gyrus. Our results reveal that delusions are relatively common in dementia, particularly in behavioural-variant frontotemporal dementia. These symptoms may lead to delayed or inaccurate diagnosis, and therefore increased awareness of the neuropsychiatric features of dementia is important. Patients with delusions appear to have more widespread impairment and may be good candidates for targeted for symptom management.
DR SIVA PURUSHOTHUMAN Brain And Mind Centre & University Of Sydney Autophagy-lysosomal-protein changes in latestage pathologically-confirmed human postmortem brains of Alzheimer’s compared with Lewy body diseases Sivaraman Purushothuman1 , Tony Hsiao1 & Glenda Halliday1,2 1 Brain & Mind Centre, University of Sydney, Camperdown, NSW 2050, Australia, 2 Neuroscience Research Australia and University of New South Wales, Randwick, NSW, Australia Lysosomal impairment is implicated to produce various neurodegenerative pathogenic events in Alzheimer (AD) and Lewy body diseases (LBD) patients. This is the first study to explore the differences in autophagy-lysosomal proteins across AD, LBD and mixed-type cases since >40% of cases have overlapping disease-specific pathologies that may lead to diagnostic confusion. Pathologically-confirmed post-mortem brains with agerelated changes of “pure” AD (amyloid-ß; N=18), “pure” LBD (Lewy bodies; N=19), mixed-type (AD+LBD; N=20), and controls (N=20) from superior temporal (STC; mainly affected) and occipital cortices (OC; variably affected) cases without neuropathology-specific mutations or cerebrovascular diseases were selected. Protein levels of lysosomal and autophagy-related proteins were assessed using immunoblotting. Multivariate and one-way ANOVA with Tukey’s multiple comparison statistical analyses were performed. Age, gender or postmortem delay did not affect the results. Lysosomal enzymes such as glucocerebrosidase and Cathepsin K were significantly (p<0.05) reduced in both regions and all three disease groups versus controls, while Cathepsin D level was significantly (p<0.05) increased only within the OC. In both AD brain regions, lysosomal-Associated membrane protein 1 (LAMP1) was significantly (p<0.01) reduced from controls. Against controls, LAMP2 was increased (p<0.0001) in AD for OC only, while LAMP3 was reduced (p<0.01) in AD and mixed-type cases within OC region only. Autophagosome proteins of Beclin1 and p62 in both brain regions were significantly reduced in all three disease groups versus controls. Neurons (assessed using NeuN and TubulinIIIß) in STC and OC were reduced (p<0.05) in AD only. Results revealed that lysosome-Associated proteins need closer examination across similar diseases.
DR RACHEL WONG University of Newcastle Maintaining the blood-brain barrier is critical to protect the ageing brain Safeguarding the homeostasis of the brain’s microenvironment, cerebral endothelial cells form a bloodbrain barrier (BBB) of specialised tight junctions in which a complex system of transporters regulates bidirectional trafficking of essential substrates and metabolites of neuronal activity. This unique barrier also keeps neurotoxic substances and pathogens out of the central nervous system. Therefore, a dysfunctional BBB has been thought to compromise brain function, including cognition, but reliable human data are lacking. Simple quantifiable methods and biomarkers are needed to evaluate BBB integrity in the living human brain. The current imaging method for BBB integrity is via the introduction of gadolinium, a contrast agent, used in magnetic resonance imaging. However, the resolution is insufficient to discriminate between regions and the results are only positive in people with severely compromised BBB function such as in stroke, brain tumours, multiple sclerosis and meningitis, as BBB permeability is typically much lower in the normal ageing brain. Using enhanced contrast, recent research has shown that BBB disruption begins at the hippocampus during normal human ageing and worsens in those with mild cognitive impairment1; similarly a five-year study involving 161 older adults showed that people with severe memory problems had the worse BBB function independent of the presence of abnormal proteins amyloid and tau2, thereby implicating microvascular dysfunction in the initial pathogenesis. A growing body of evidence suggest that early vascular dysregulation associated with cerebral hypoperfusion and impaired haemodynamic responses are already detectable before the manifestation of cognitive decline and/or other brain pathologies. Yet, little attention has been given to this aetiology. The clinical evidence of whether BBB dysfunction and its sequelae are reversible with treatment is lacking. We and others have demonstrated that non-pharmacological treatments such as nutrients from food ingredients and exercise can restore cerebral vasodilator responsiveness, a key index of cerebrovascular function, which is associated with enhanced cognitive performance in older adults without dementia. Mechanisms of action of nutrients in reversing BBB deficits have also been demonstrated in preclinical models of diabetes, another risk factor for developing dementia. In this proposed round table event, dementia researchers from both preclinical and clinical research spheres will come together for a high-level discussion regarding the suitability, reliability and affordability of biomarkers such as S100-beta to detect early changes in BBB function in humans that can be used in clinical trials to evaluate various non-pharmacological strategies including lifestyle and dietary changes to prevent or delay accelerated brain ageing. We will also discuss strategies to boost awareness of the importance of optimising the health of the cerebral microvasculature for healthy brain function in the research field as well as to the community. Clinicians and representatives from relevant government and NGOs including Diabetes Australia will also be invited to participate.
PROFESSOR IRENE BLACKBERRY LaTrobe University Living well with dementia: what does the future hold for dementia research and knowledge exchange in rural and regional Australia? In 2018, there were an estimated 436,366 Australians living with dementia and this number is expected to rise to 589,807 by 2028 (1). Dementia creates complex challenges and therefore people living with dementia and their care partners (spouse, family and friends) need access to a variety of medical and social care and support services, in the community as well as in residential care. In rural areas, there is frequently a reduced range of available services and rural people might be obliged to travel longer distances to access services, or there might be reduced availability of services close to home. Given the tenacious challenges faced by rural communities, the John Richards Centre for Rural Ageing Research, at the La Trobe Rural Health School, La Trobe University, has begun to engage in a program of research to better understand support needs and to trial innovative solutions for increasing support for carers and people living with dementia in rural and regional areas. There are five key projects that the John Richards Centre is currently undertaking, in collaboration with communities, health service partners, and Australian and International researchers: 1. Virtual Dementia Friendly Rural Communities (Verily Connect) This project is trialling custom-designed and freely available online technologies to make information more accessible and to increase support for carers. Twelve rural communities across Victoria, New South Wales, and South Australia are participating. In addition, volunteers in each community provide face-to-face help to carers in using the technologies. 2. HelpDEM Volunteers are matched with carers of people living with dementia in two rural communities in Victoria. The trained volunteers serve as a resource that carers can access for information, social and emotional support, friendship, and ideas. 3. Webster Rural and Regional Dementia Care Project This three-year research initiative is funded through the bequest of Mr Gordon Webster. The project aims to improve dementia care pathways within rural and regional Victoria, with emphasis on developing innovative and sustainable care of residents of Bendigo and surrounding regions. 4. Exploring rural community capacity to enable voluntary and civic participation for people living with dementia This project aims to determine the potential areas of volunteer engagement for people living with dementia within rural and regional community organisations. 5. Implementing and sustaining Cognitive Screening in Rural and Regional Health Services This project focusses on overcoming barriers and harnessing facilitators to introduce, implement and sustain effective Cognitive Screening in rural and regional Health Services. In this round table discussion, researchers and consultants involved with these five projects, will use learnings from the research to highlight challenges, successes, and possible future directions for dementia research in rural areas. A specific focus will be to develop an ongoing Special Interest Group centring on dementia care, support, and research in rural and regional communities.
DR ADAM BENTVELZEN Centre For Healthy Brain Ageing (CHeBA), University Of New South Wales The TICS-M telephone cognitive screen: Validation and norms from the Sydney Memory and Ageing Study Dr Adam Bentvelzen1 , Dr John Crawford1 , Mr Adam Theobald1 , Ms Kate Maston2, Dr Melissa Slavin3, Dr Simone Reppermund1,3, Dr Kristan Kang1 , Dr Katya Numbers1 , Dr Henry Brodaty1,4, Dr Perminder Sachdev1 , Dr Nicole Kochan1 1 Centre For Healthy Brain Ageing (CHeBA), School of Psychiatry, University Of New South Wales, Sydney, Australia, 2Black Dog Institute, Sydney, Australia, 3Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, Australia, 4Dementia Centre for Research Collaboration (DCRC), School of Psychiatry, University of New South Wales, Sydney, Australia
Phone-based cognitive screens such as the Telephone Interview for Cognitive Status (TICS) can potentially reduce the barriers and costs of assessing cognition in older adults. Existing normative data for the TICS may lack sensitivity as previous studies have not used regression-based demographic corrections, accounted for cases with subsequent dementia, or estimated reliable change in a large and comprehensively assessed sample of older adults. Furthermore, validation of clinically relevant psychometric properties is lacking. Here, we address these gaps using the TICS-M (modified 13-item, 39-point version) and provide an online norms calculator for clinicians and researchers. Participants were 617 community-living older adults aged 71 to 91 participants from the Sydney Memory and Ageing Study (M = 79.66 years, 11.72 years of education). TICS-M total scores (M = 24.20, SD = 3.76) decreased with age and increased with higher education levels. The robust normative sample, which excluded incident dementia cases, scored higher on the TICS-M and with less variability than the whole sample, particularly at older ages and lower educational levels. An online calculator https://cheba.unsw.edu.au/ research-groups/neuropsychology is provided to compute regression-based norms and reliable change statistics. TICS-M scores correlated more highly with ACE-R (.80) than with MMSE (.70) and showed moderate-strength correlations (r = .30) with neuropsychological tests despite the latter being tested non-contemporaneously. Overall, the TICS-M demonstrated sound validity against well established and diagnostically sensitive cognitive screens and neuropsychological tests. The regression-based and robust normative data provided will help improve the sensitivity, accessibility and cost-effectiveness of cognitive testing with older adults.
DR PRASHANT BHARADWAJ School of Medical and Health Sciences, Edith Cowan University IU1, a selective inhibitor of deubiquitinating enzyme USP14 inhibits Aß toxicity in neuronal cells Bharadwaj P 1, 2 , Hone E 1, Martins R 1, 3, 4 1 Centre of Excellence in Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Ralph and Patricia Sarich Neuroscience Research Institute, Edith Cowan University, WA, Australia, 2 Curtin Health Innovation Research Institute, School of Pharmacy and Biomedical Sciences, Curtin University, Bentley WA, Australia, 3 School of Biomedical Science, Macquarie University, Sydney NSW, Australia, 4 School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands WA, Australia https://www.nnidr.gov.au/sites/default/files/files/Abstracts_online.pdf Autophagy is a vital intracellular catabolic pathway for misfolded proteins and an attractive therapeutic target for neurodegenerative diseases including Alzheimer’s disease (AD). We have previously shown that enhancing autophagy reduced Aß accumulation and toxicity in cells and improved cognition in an AD mouse model. A wide range of small molecules targeting multiple cell functions have now been developed to modulate autophagy. Assessing the neuroprotective effects of modulators against Aß toxicity would further our understanding of their protective mechanisms and aid development of novel treatments for AD. Therefore, the main aim of this project is to identify potent autophagy modulators that protect against Aß induced neuronal cell death. In this study, we used the MC65 cell line to model Aß accumulation and toxicity. MC65 is a well-established human CNS derived cell line that generates Aß by ?-secretase cleavage from a stably transfected C99 fragment of the amyloid precursor protein (APP). Using this cell line as a platform, we screened an autophagy compound library containing 156 small molecules for inhibition of Aß toxicity. We observed inhibition of Aß induced cell death by the ion channel blockers carbamazepine, omeprazole and IU1, a selective inhibitor of deubiquitinating enzyme USP14. Overall, IU1 was identified as the most potent compound showing a marked 40% increase in cell survival in MC65 cells producing Aß. Recent studies show that IU1 regulates autophagy and degradation of prion aggregates in cells. This suggest that its protective effect in MC65 cells is possibly through the upregulation of Aß protein clearance. Our findings demonstrate a novel role for IU1 in reducing Aß induced toxicity. Further investigation of its protective effects will be essential in determining its therapeutic potential in AD.
