Neurology

Telestroke is an example of technology facilitating the delivery of time-dependent therapies in regional Australia

Carlos Garcia‐Esperon · Christopher F Bladin · Timothy J Kleinig · Helen Brown · Jennifer J Majersik · Andrew Wesseldine · Kenneth Butcher

High prevalence and associated health care and social costs demand a change in health care paradigms for functional neurological disorders

Elizabeth Pepper · Adith Mohan · Kenneth Butcher · Mark Parsons · Jackie Curtis

To the Editor: The socio‐economic modelling of the impact of a hypothetical disease‐modifying treatment (DMT) for Alzheimer disease by the National Centre for Social and Economic Modelling (NATSEM)1 is an interesting contribution to what is a critical question for policymakers: how effective does a new antidementia treatment need to be to justify a given cost to the community? Unfortunately, the report does not address this, and several internal deficits call into question the conclusions: • The disease progression pathway lacks backwards transitions. It is commonly understood that mild cognitive impairment is an unstable diagnostic state; individuals are at higher risk for transition to dementia, but a predictable proportion also spontaneously revert back to cognitive normality.2 • The durability of DMT efficacy is unrealistic. It is implausible to assume that a 12‐month treatment with an anti‐amyloid will deliver lifelong cognitive benefits after cessation. In the EMERGE and ENGAGE trials,3 the treatment was for the duration of the trials (18 months), and it is generally accepted that this form of treatment will require infusions for years. • The clinical efficacy of DMT is unfounded. Scientific opinion is divided as to whether modification of cerebral amyloid burden has clinical benefits on cognition or daily function. Further, there is no good reason to assume that a 23% relative difference on the continuous measure of cognitive decline observed in EMERGE — incidentally, not replicated in the identically designed ENGAGE trial3 — will translate to a relative difference in categorical transitions between mild cognitive impairment and mild or moderate dementia. Given this is the main driver of projected cost savings, assuming a 25% reduction in such transitions is unrealistic4 and, surprisingly, not subject to sensitivity analysis. • The adverse costs of DMTs are not modelled. It is not appropriate to model presumed clinical benefits of a hypothetical DMT without accounting for the personal, medical and social cost of their documented adverse effects, including cerebral oedema, brain haemorrhage, and falls.2,5 Given that the list price of any such DMT to the health system was also deliberately not modelled, NATSEM is encouraged to address these concerns in a revised report.

Michael Valenzuela

The Australian and New Zealand living stroke management guidelines provide timely, evidence-based updates to recommendations

Coralie English · Kelvin Hill · Dominique A Cadilhac · Maree L Hackett · Natasha A Lannin · Sandy Middleton · Annemarei Ranta · Nigel P Stocks · Julie Davey · Steven G Faux · Erin Godecke · Bruce CV Campbell

Clinicians and policymakers should develop measures that further mitigate the risk of sport-related repetitive head injury

Catherine M Suter · Andrew J Affleck · Maggie Lee · Alan J Pearce · Linda E Iles · Michael E Buckland

Aducanumab, a controversial Alzheimer disease therapeutic with questionable efficacy, is under Therapeutic Goods Administration review

Andrew Gleason · Scott Ayton · Ashley I Bush

Australia has the clinical and scientific expertise to introduce mitochondrial donation in a highly regulated environment, but requires changes in legislation to adopt this innovative technology

Marie A Dziadek · Carolyn M Sue

What Australia can learn from overseas guidelines

Katherine Sewell · Tamara Tse · Geoffrey A Donnan · Leeanne M Carey

A 57-year-old man presented with left facial droop and dysarthria due to a multiterritory ischaemic stroke affecting the right posterior and middle cerebral arteries

Jessica V Yao · Subodh B Joshi · John G Morgan · Melissa GY Lee

A previously healthy 45-year-old woman presented with a history of sudden-onset right hemiparesis and dysarthria while walking

Mário LM Silva Júnior · Tereza EFC Albuquerque · Eduardo S Melo

A previously well, 42-year-old man presented with a 4-day history of sudden onset, bilateral, occipital headache, 4 weeks after returning from a holiday in Thailand

Simon Smith · Ian Wilson · Lea Starck · Enzo Binotto · Jennifer Ho · Joshua Hanson

It is critical primary care clinicians dedicate specific attention to the management of both depression and insomnia when they co-occur

Alexander Sweetman · Leon Lack · Emer Van Ryswyk · Andrew Vakulin · Richard L Reed · Malcolm W Battersby · Nicole Lovato · Robert J Adams

Australia’s narcolepsy management is inadequate by international standards and should be aligned with that of other first class health services

Sheila Sivam · Ksenia Chamula · John Swieca · Simon Frenkel · Bandana Saini

A 75-year-old man presented with right hemiparesis secondary to a left thalamic haemorrhage

Julia Lim · Yi Chao Foong

Objective: To examine relationships between changing general practitioner after entering residential aged care and overall medicines prescribing (including polypharmacy) and that of psychotropic medicines in particular. Design: Retrospective data linkage study. Setting, participants: 45 and Up Study participants in New South Wales with dementia who were PBS concession card holders and entered permanent residential aged care during January 2010 ‒ June 2014 and were alive six months after entry. Main outcome measures: Inverse probability of treatment‐weighted numbers of medicines dispensed to residents and proportions of residents dispensed antipsychotics, benzodiazepines, and antidepressants in the six months after residential care entry, by most frequent residential care GP category: usual (same as during two years preceding entry), known (another GP, but known to the resident), or new GP. Results: Of 2250 new residents with dementia (mean age, 84.1 years; SD, 7.0 years; 1236 women [55%]), 625 most frequently saw their usual GPs (28%), 645 saw known GPs (29%), and 980 saw new GPs (44%). The increase in mean number of dispensed medicines after residential care entry was larger for residents with new GPs (+1.6 medicines; 95% CI, 1.4‒1.9 medicines) than for those attended by their usual GPs (+0.7 medicines; 95% CI, 0.4‒1.1 medicines; adjusted rate ratio, 2.42; 95% CI, 1.59‒3.70). The odds of being dispensed antipsychotics (adjusted odds ratio [aOR], 1.59; 95% CI, 1.18‒2.12) or benzodiazepines (aOR, 1.69; 95% CI, 1.25‒2.30), but not antidepressants (aOR, 1.32; 95% CI, 0.98‒1.77), were also higher for the new GP group. Differences between the known and usual GP groups were not statistically significant. Conclusions: Increases in medicine use and rates of psychotropic dispensing were higher for people with dementia who changed GP when they entered residential care. Facilitating continuity of GP care for new residents and more structured transfer of GP care may prevent potentially inappropriate initiation of psychotropic medicines.

Heidi J Welberry · Louisa R Jorm · Andrea L Schaffer · Sebastiano Barbieri · Benjumin Hsu · Mark F Harris · John Hall · Henry Brodaty

Responses to the health care needs of this vulnerable group have improved, but further progress is needed

David I Ben‐Tovim · Kim Vien

A patent foramen ovale (PFO) is an interatrial shunt, with a prevalence of 20–34% in the general population. While most people do not have secondary manifestations of a PFO, some reported sequelae include ischaemic stroke, migraine, platypnoea–orthodeoxia syndrome and decompression illness. Furthermore, in some cases, PFO closure should be considered for patients before neurosurgery and for patients with concomitant carcinoid syndrome. Recent trials support PFO closure for ischaemic stroke patients with high risk PFOs and absence of other identified stroke mechanisms. While PFOs can be associated with migraine with auras, with some patients reporting symptomatic improvement after closure, the evidence from randomised controlled trials is less clear in supporting the use of PFO closure for migraine treatment. PFO closure for other indications such as platypnoea–orthodeoxia syndrome, decompression illness and paradoxical embolism are based largely on case series with good clinical outcomes. PFO closure can be performed as a day surgical intervention with high procedural success and low risk of complications.

Kenneth K Cho · Shaun Khanna · Phillip Lo · Daniel Cheng · David Roy

Intensive metabolic control reduces the incidence and progression of diabetes‐related micro‐ and macrovascular complications.1,2 Nevertheless, the risk of developing cardiovascular disease is higher for people with diabetes,3 although cardiovascular disease incidence rates are generally declining more rapidly for people with diabetes than for other people.4,5 We analysed hospital discharge data from the Victorian Admitted Episode Dataset6 for 1 January 1999 – 31 December 2016. We identified incident cases of three cardiovascular disease complications (acute myocardial infarction [AMI], stroke, and heart failure) by International Statistical Classification of Diseases, tenth revision, Australian modification (ICD‐10‐AM) codes. Data for 1999‒2003 were examined to ensure that admissions during the observation period (2004‒2016) were index admissions for the specific complication, but were not included in our main analysis. Admission rates were separately calculated for people with type 1 or type 2 diabetes (numbers of people with diagnosed diabetes, by year, were obtained from the National Diabetes Services Scheme, which captures 80–90% of diabetes diagnoses7) and for people without diabetes (derived from Australian Bureau of Statistics census data8). We analysed changes in admission rates by Joinpoint regression (https://surveillance.cancer.gov/joinpoint); points at which changes in the direction or magnitude of linear trends were statistically significant (P < 0.05) were determined with permutation tests. Each trend segment was described by an annual percentage change (APC), and the change for the entire study period as the mean APC (further details: online Supporting Information). The study was approved by the St Vincent’s Hospital Melbourne Human Research Ethics Committee (HREC/18/SVHM/146). A total of 382 107 patients were admitted to Victorian hospitals during 2004–2016 with cardiovascular complications: 278 991 without diabetes (73%), 3645 with type 1 diabetes (1%), and 99 471 with type 2 diabetes (26%). AMI admission rates declined during this period for people with type 1 (mean APC, –7.7%; 95% confidence interval [CI], –13.4% to –1.5%) or type 2 diabetes (mean APC, –11.4%; 95% CI, –13.0% to –9.9%), as well as for people without diabetes (mean APC, –5.0%; 95% CI, –6.7% to –3.4%) (Box 1, Box 2). Stroke admission rates declined significantly during 2004–2016 for people with type 1 diabetes (mean APC, –7.2%; 95% CI, –12.2% to –1.9%); for people with type 2 diabetes, rates declined during 2005–2011 and 2014–2016, but not during 2011–2014 (overall change: –11.9%; 95% CI, –17.0% to –6.5%). For patients without diabetes, the decline during 2005–2014 was significant (mean APC, –4.1%; 95% CI, –5.8% to –2.3%), but not during 2015–2016 (Box 1, Box 2). Admissions for heart failure declined during 2004–2016 for people with type 1 diabetes (mean APC, –10.3%; 95% CI, –14.1% to –6.4%) or type 2 diabetes (mean APC, –9.2%; 95% CI, –11.0% to –7.3%), and also for people without diabetes (mean APC, –2.8%; 95% CI, –4.1% to –1.5%) (Box 1, Box 2). As hospital discharge coding data do not provide information on metabolic control or medication use, we could not assess whether cardiovascular risk factor modification and use of specific medications were associated with changes in admission rates. We also lacked information on disease duration for patients with hospital‐coded diabetes. Further, we have counted admissions of any patients who had presented with complications before 1998 (ie, outside our 5‐year clearance period) as incident admissions; these patients would be at very high risk of further admissions, and their inclusion may have inflated the admission rates we report for the observation period of our study. Few recent studies have assessed outcomes for all three cardiovascular complications in a single investigation. Cardiovascular complication‐related admissions to Victorian hospitals declined during 2004–2016 more rapidly for people with diabetes than for those without diabetes. The relatively greater absolute decline in the numbers of admissions of people with diabetes may be related to the fact that they are considered to be at high risk for cardiovascular disease and are therefore treated more aggressively; the scope for reducing risk with multifactorial target‐driven interventions is greater in these patients. Nevertheless, admission rates for cardiovascular complications of people with diabetes remain relatively high. Box 1 – Age‐ and sex‐adjusted admission rates for cardiovascular complications (with 95% confidence intervals), Victoria, 2004–2016, by diabetes status of patients Box 2 – Annual percentage change (APC) in admissions for cardiovascular complications, Victoria, 2004–2016, by diabetes status Change in event rate, 2004–2016* Change in event rate, by period* Cardiovascular complication and diabetes status Admissions Overall change (95% CI) Mean APC (95% CI%) Mean APC (95% CI) Acute myocardial infarction No diabetes 114 965 –24.8% (–24.9% to –24.7%) –5.0% (–6.7% to –3.4%) — Type 1 diabetes 1272 –7.7% (–8.8% to –6.7%) –7.7% (–13.4% to –1.5%) 1. 2005–2009: +7.0% (–9.7% to +22.8%) 2. 2009–2016: –15.1% (–21.3% to –8.7%) Type 2 diabetes 15 278 –69.0% (–69.0% to –68.8%) –11.4% (–13.0% to –9.9%) — Stroke No diabetes 52 320 –10.9% (–13.6% to –10.6%) –1.7% (–4.9% to +1.5%) 1. 2005–2014: –4.1% (–5.8% to –2.3%) 2. 2014–2016: +9.6% (–10.2% to +33.8%) Type 1 diabetes 504 –44.4% (–50.0% to –41.4%) –7.2% (–12.2% to –1.9%) — Type 2 diabetes 17 440 –68.0% (–68.0% to –67.9%) –11.9% (–17.0% to –6.5%) 1. 2005–2011: –14.7% (–17.6% to –11.7%) 2. 2011–2014: +5.8% (–19.0% to +38.2%) 3. 2014–2016: –26.1% (–39.8% to –9.2%) Heart failure No diabetes 135 524 –22.2% (–22.3% to –22.2%) –2.8% (–4.1% to –1.5%) — Type 1 diabetes 1393 –55.1% (–58.6% to –52.4%) –10.3% (–14.1% to –6.4%) — Type 2 diabetes 52 831 –67.3% (–67.4% to –67.3%) –9.2% (–11.0% to –7.3%) — * Adjusted for age and sex. Event rates for 2004 and 2016 are included in the expanded version of this table in the online Supporting Information.

Katerina V Kiburg · Andrew I MacIsaac · Andrew Wilson · Vijaya Sundararajan · Richard J MacIsaac

To the Editor: Sexual incidents involving patients in hospitals are prevalent and are distressing for patients and staff alike, but they are poorly managed.1 Such incidents are frequently perpetrated by people with acute mental illness (eg, mania, psychosis), substance misuse, personality vulnerabilities, and cognitive impairment (eg, delirium, dementia). Sexual incidents span the age range, although lack of staff's understanding of sexuality and sexual behaviour in older adults2 mandates practice improvement. Sexual safety is defined in health care settings as “recognition, maintenance and mutual respect of the physical [including sexual], psychological, emotional and spiritual boundaries between people”.3 Sexual incidents include sexual offences (criminal offences such as sexual assault) and inappropriate sexual behaviour, ranging from suggestive language to removing clothing, exposure, and public masturbation. State public mental health services have sexual safety policies and guidelines, but no such policies exist for general hospitals. The scholarly literature is similarly limited. Our experience of sexual safety in health care can be described as “a neglected area, there is no training, no one is talking about it and there seems little interest until something happens,” particularly involving older people.1 A hypothetical case based on clinical experience (Box) demonstrates the trivialisation and minimisation of sexual incidents in health care and the associated risks and ramifications. This phenomenon is aligned with the “dirty old man” stereotype, a reflection of ageist societal attitudes towards sex in older people as inappropriate, shameful or funny.4 Consequences of these attitudes for clinical management include poor documentation and communication, inconsistent responses to patient behaviour, and multiple victims, particularly staff. Sexual harassment is both under‐reported by staff5 and dealt with superficially, despite having significant effects on physical and psychological health and burnout.6 These issues are compounded in aged care, where staff ignore or minimise the impact of sexual behaviour, which is often excused by cognitive impairment4 or dismissed as harmless due to frailty or advanced age.5 Aged care staff may feel shame, guilt, confusion and even responsibility for causing the behaviour.5 Conversely, a tension exists between a cognitively impaired person’s right to sexual expression and the health care worker’s right to a safe workplace. Education of health care staff and development of guidelines with response pathways are needed to ensure sexual behaviour is understood and dealt with consistently and respectfully.4 In this situation, ageism trivialises risk and harm, which may have an adverse impact on a safe health care environment. Box – Hypothetical case based on clinical experience describing the trivialisation and minimisation of sexual incidents in health care and the associated risks and ramifications Warren is a 73‐year‐old single man treated in a geriatric ward in a general hospital for delirium. He has a history of cognitive impairment due to long term alcohol misuse and has a guardian for medical decision making. The delirium is slow to resolve and after a few weeks he starts propositioning nursing staff for sex and making sexual comments. Warren often has an erection when nurses assist with personal care and he masturbates on his bed, visible to patients, visitors and staff. He is moved to a single room and a minimum of two staff are present for any clinical interaction. Three female staff members are grabbed on their breasts while providing Warren with care. This is inconsistently documented in his medical record. His sexual behaviour is discussed with some derision in staff handovers. There is no disclosure of his behaviour to non‐ward staff involved in his care (eg, consulting teams), among whom further assaults occur. A security guard is stationed at his door to keep him in his room. He is commenced on a specific serotonin reuptake inhibitor with the aim of reducing libido. Warren continues to be sexually disinhibited in behaviour and comments, a barrier to securing a nursing home placement. General principles: Management must include behaviour assessment and addressing underlying issues (eg, delirium, unmet sexual needs) with practical environmental and governance measures such as formal handover of behaviour between shifts and for consulting teams and clinicians, clear and easily accessible management plans, and support for staff, visitors and other patients. Consider the use of sexual harassment measurement tools for reporting and awareness raising.

Anne PF Wand · Carmelle Peisah

A virtual brain bank could maximise the potential of brain donation by extending the core physical bank to include existing repositories of clinical tissues and data Brain banking, whereby post mortem brains are harvested, processed, stored and made available to facilitate health and medical research, provides scientists with an unparalleled resource for macroscopic, microscopic and molecular investigations into many brain conditions. The human brain is seen as the final frontier of scientific research, with many cognitive processes and neurological diseases exclusively manifesting in humans. This uniqueness has been postulated as an explanation for why many brain disease drug leads do not progress past the acknowledged “valley of death” whereby success in animals is not translated to human clinical trials.1 For many brain researchers, human post mortem tissue is therefore preferred or essential for their investigations. The importance and utility of whole brain banking was recently demonstrated by a collection of articles in the Handbook of Clinical Neurology.2 In particular, Zielke and Mash, in a wide ranging review of bank management and operations, posed the question of whether “the value of the brain can be enhanced by collecting other tissues”.3 Here we make the case for the affirmative by describing how brain banking can, by aligning with broader biobanking initiatives, enhance the value of brain tissue for both current and “future patients and society”3. State of play Biobanks that collect tissue other than brains are typically embedded in clinical workflows, whereby collection and characterisation of residual tissue for biobanking takes place in parallel with tissue required for clinical purposes. However, in our experience in Australia, brain removal is not routinely included as part of an autopsy or post mortem examination. Autopsies themselves are now uncommon, even within the forensic setting;4 reasons for this are varied and include advances in ante mortem diagnosis propelled by imaging technologies, a belief that autopsy reports fuel malpractice lawsuits, logistic issues, and poor reimbursement rates for pathologists.5 It is now common in Australia for pathology specialists to complete their training without having conducted a post mortem examination, with the future pathology workforce destined to be demarcated into those who have and have not received training to conduct an autopsy. Today, brain removal is largely confined to the setting of brain donor programs, established to recruit and clinically characterise donors with specific diseases and, more rarely, controls.4 One reason for the decline in clinical and forensic autopsies performed is the increasing quality of modern imaging techniques.6 Similarly, ‐omic approaches, particularly metabolomics, for obtaining brain‐specific information7,8 are being increasingly applied to clinically available tissues such as serum and cerebrospinal fluid. Brain organoids developed from patient‐derived stem cells are also a promising in vitro model.9 At present, neuropathological confirmation of disease provides a “ground truth” but over time, refinement of imaging, peripheral biomarkers and in vitro models could diminish the importance of whole brain banking in isolation. For brain donor programs, brain removal logistics are often complex and costly, with reliance on in‐kind support from funeral directors, clinicians and mortuary staff. After tissue harvesting, brains require specialist processing expertise and large storage areas, resulting in increased labour and space costs. The timing and finality of brain removal can also have an impact on the collection of longitudinal clinical data, which may require medical records departmental input and/or facilitation by family members. The predicted rise in the morbidity and mortality of dementia and reported increases in the prevalence of mental health in Australia provide convincing evidence of the need for research into risk factors and therapies for neurological diseases. Currently, whole brain banks typically characterise and collect in the vicinity of 1000 donors. Cohorts of pathologically confirmed cases and controls tend to be an order of magnitude smaller than that required to efficiently carry out genetic analyses such as genome‐wide association studies. In the future, even larger cohorts will be required to examine the probable gene–environment interactions that confer risk for many sporadic brain diseases.10 We propose a novel brain banking strategy that maximises the potential of brain donation by extending the core physical bank to include existing repositories of clinical tissues and data, creating a virtual brain bank. This would not only benefit brain researchers but also researchers investigating potential interactions between the brain and other vital organs. A next‐generation solution Rather than competing with alternative technologies, a next‐generation (virtual) brain bank could incorporate these technologies into a suite of products offered to researchers. Although brain donor programs already strive to maximise the clinical and demographic information available for each participant (Box 1), an integrated brain bank could extend their involvement to more comprehensive clinical data collection, generation and analysis. This would make samples and derivatives such as serum, DNA, images and genetic/‐omic data available for researchers, in addition to brain tissue.3 We suggest extending this approach beyond tissues from donors themselves to include collaborations with existing brain‐specific clinical tissue banks such as the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD). The NCRAD stores clinical non‐brain tissue samples from over 90 000 participants — in the order of two degrees of magnitude larger than the number of donors in most brain banks (Box 2). These samples have been subjected to multi‐omic analyses, and with associated imaging data have provided key insights into Alzheimer disease.11 Their level of analysis on ante mortem samples would allow an unprecedented depth of clinicopathological correlations if a subset of participants consented to brain autopsy. Extending this scenario, a next‐generation brain bank could be integrated into multipurpose biobanking initiatives. The size and intensive phenotyping within prospective cohort studies such as the UK Biobank (https://www.ukbiobank.ac.uk/), which hosts 500 000 participants, offers data on a rich source of age‐related brain diseases over time. Furthermore, there is already genetic, neuroimaging and neuropsychological testing data available from neurologically normal volunteers, enabling brain bank personnel to use their skills and expertise to provide risk factor insights as well as directing subsequent mechanistic studies in post mortem brain tissue (Box 2). In this scenario, the brain bank could remain responsible for the characterisation and provision of brain‐related tissue and data, but be just one component in an integrated resource that characterises the lifespan of an individual donor. This would not only allow brain banks to contribute to research on brain diseases for living patients, but would also create bi‐directional synergies with researchers of other diseases; that is, “brain and body” biobanking. For example, diabetes has been shown to have a central component,12 dementia and cardiovascular disease share common risk factors,13 and there are fascinating inverse associations between neurodegenerative diseases and cancer.14 In the integrated biobank envisaged, a dynamic consent model could be employed whereby an initial permission to contact could be followed by consent for provision of data and clinical samples, and eventually by consent for post mortem brain donation. A dynamic consent model also encourages deeper participant engagement. Ultimately, only a small proportion of participants are likely to become whole brain donors (Box 2), meaning direct clinicopathological correlations will always be limited. However, the workflow of a more inclusive brain and body banking model would enable complementary resources to be offered to a broader range of scientists. The 2016 National Research Infrastructure Roadmap15 recommended investment into collaborative and effective biobanking in Australia, with the government response recommending a national biobank scoping study. One possible outcome of a biobank scoping study is for the federal government to re‐engage in funding single or multi‐disease initiatives on a state or national basis. For example, the 45 and Up Study that follows approximately 250 000 middle aged community volunteers in New South Wales is a data‐linked cohort study with the potential to underpin such a brain and body biobank.16 Importantly, data linkage with routinely collected clinical and administrative data in the Australian health system gives further credence to the integration of brain banking with state or nation‐wide biobanking initiatives where clinical laboratory test results, medication history and comorbidity data can validate or extend self‐reported information. A multi‐focus bank or any research infrastructure becomes challenging to fund after initial investments. The integration of expertise across diseases and an intramural science program that kick starts traditional collaborations and commercial opportunities should have a favourable impact on the value proposition for current and future investors. Governance will be the key ingredient for success, but as with the multi‐focal nature of the proposed biobank, the board, science advisory committee and management team should look outside traditional professional boundaries for their representation. Certainly, a modern biobank needs buy‐in from state and federal health authorities, but it should also include representatives from the business community, patient advocacy groups and health practitioners to promote bi‐directional communication to known and as yet unrealised stakeholders. It has been suggested that to be most effective, biobanking needs to change its modus operandi from a static operation that banks tissue indefinitely to one that is actively involved in the research process — a so‐called biolibrary. By integrating with wider biobanking initiatives, next‐generation brain banks can contribute to the clinical, pathological and clinicopathological characterisation of a range of tissues and data for researchers of all disease interests. Importantly, a virtual brain bank or brain and body biolibrary will create future research synergies that otherwise would not be achieved. Box 1 – Schematic diagram showing a typical brain bank operating in conjunction with a brain donor program for a specific disease K = 1000. Box 2 – Schematic diagram of an integrated brain biobank with capacity to combine with and leverage wider biobanking endeavours (ideally suited to sporadic brain diseases with multi‐factorial aetiologies) K = 1000.

Amanda Rush · Greg T Sutherland

In a new MS diagnosis, immunisation status may be overlooked — careful planning from early in the treatment course is key Multiple sclerosis (MS) is an autoimmune disorder treated with immunomodulatory or immunosuppressive disease‐modifying therapies (DMTs). Immunosuppression predisposes to infection risk, including opportunistic infections; a higher long term risk of some infection‐related malignancies is also likely. Infections in patients with MS may result in increased relapses, functional decline and pregnancy complications.1 Immunisations play a critical role in preventing viral and bacterial infections, and in the setting of DMTs, they require careful and individualised planning from early in the treatment course. Here we provide an Australian perspective on vaccine safety and efficacy when given with DMTs. General vaccination considerations in patients with MS The immunisation status of patients should be considered at the time of MS diagnosis. Standard investigations before DMT initiation are highlighted in Box 1. A full course of vaccinations should be considered for non‐immune patients before commencing a DMT; this is sometimes forgotten in the urgency of managing a new MS diagnosis. Inactivated (non‐live) vaccines contain a killed/inactivated or subunit/conjugate of the pathogen and can be safely administered with DMTs. The immunogenicity of these vaccines when used with DMTs has not been conclusively established. Live vaccinations use an attenuated viral or bacterial strain and are contraindicated with most DMTs because of the risk of disseminated infection when used in immunocompromised states.3 Administration of live vaccines is recommended before DMT commencement (Box 2). Routine vaccinations are not associated with increased MS relapse risk,10 although the risk of relapse associated with yellow fever vaccination remains unclear.11 Immunisations administered in accordance with local guidelines are considered the best strategy for minimising the risk of infections that could trigger MS relapses.9,12 In patients experiencing clinically significant relapses, delaying vaccine administration has been suggested until patients have stabilised and show signs of improvement (typically 4–6 weeks).12 Additional consideration is required for women with MS who are planning a pregnancy. Women should receive live vaccinations before conception to prevent adverse pregnancy outcomes;13 however, DMT cessation to allow vaccination before conception is often not feasible. Vaccination should therefore be explored as early as possible, preferably before commencement of DMT, as it may represent a one‐off opportunity. It is generally considered safe to vaccinate close immunocompetent contacts (eg, family members) of patients on DMTs without risk of disseminated infection.14 Due to the potential for disseminated infection, we recommend delaying recommencement of a DMT by at least 4–6 weeks following the final dose of a live vaccine. Should a patient on a DMT require live vaccines, treatment cessation should be followed by an appropriate washout period before immunisation. No evidence‐based guidelines exist for washout periods between DMTs.15 Patients receiving DMTs with long lasting biological effects (eg, ocrelizumab, alemtuzumab, cladribine) may require prolonged treatment interruption and monitoring to ensure a return to immunocompetency before vaccination (Box 3). The risk of delayed DMT recommencement, including risk of relapse and worsening neurological disability, should be carefully considered against the benefits of immunisation. Ultimately, the long term benefits of vaccination may outweigh the short term risk of relapses. Confirming seroconversion after vaccination is sometimes advised to ensure those who do not generate adequate titres are informed about any possible risk associated with future exposure. An attenuated humoral response is seen with ocrelizumab therapy.27 However, it should be noted that serological testing is insensitive to the contribution of vaccine‐associated cellular immunity, which is likely to offer at least partial protection.29 Individual vaccinations and specific considerations Influenza (non‐live) The seasonal influenza vaccine is considered safe for patients with MS regardless of DMT exposure and is recommended annually.4 Efficacy may be reduced by some DMTs, and seroconversion is attenuated by anti‐CD20 therapy.27 Primary varicella (live) The risks associated with varicella zoster virus infection in patients with MS receiving DMTs highlight the importance of vaccination in this population.30 Vaccination should be considered before DMT commencement in patients lacking demonstrable serological immunity who have an absent or unclear history of chickenpox, shingles or vaccination.31 Varicella zoster reactivation (live) Zostavax (Merck) reduces the risk of shingles and post herpetic neuralgia; it is a larger dose of the live attenuated primary varicella vaccine and is therefore also contraindicated with DMTs.5 Vaccination should be considered 4–6 weeks before commencing any DMT; however, reimbursement in many countries is reserved for older age groups, in whom efficacy may be uncertain.7 Measles–mumps–rubella (live) The combined measles–mumps–rubella vaccine is part of childhood vaccination schemes in most high income countries. It should be administered to patients who lack immunity to any of these viruses before commencing DMT.5 Women planning future pregnancy are advised to have immunity against rubella to prevent adverse outcomes such as miscarriage and congenital defects.5 Pneumococcus (non‐live) Australian guidelines for pneumococcal vaccination are currently in flux; readers are encouraged to check the Australian immunisation handbook for up‐to‐date recommendations.5 Two non‐live vaccines against Streptococcus pneumoniae are available in Australia: a 13‐valent conjugate and a 23‐valent polysaccharide vaccine. The benefits of pneumococcal immunity are potentially significant in the MS population, and the multidose schedule should be particularly applied to patients receiving B cell‐depleting agents, or after immune‐ablative therapies.5 Hepatitis B virus (non‐live) Patients receiving DMTs enter a higher risk category for hepatitis B given their chronic condition, immunocompromise and potentially frequent health care contact.5 Other risk factors to consider include frequent close contact with blood, compromised immunity, intercourse or residence with someone infected with hepatitis B virus, having more than one sexual partner, and frequent travel. To optimise the immune response, the first of three doses should be given before DMT exposure where possible. To prevent treatment delays the remaining doses may be given after DMT commencement. Specialist referral before DMT commencement is required for patients with serological evidence of prior (core antibody positive and surface antigen negative) or chronic (surface antigen positive and/or DNA positive) hepatitis B virus infection, for surveillance and antiviral therapy to mitigate reactivation risk. This is a particular risk with fingolimod and lymphocyte‐ablative therapies. Diphtheria–tetanus–pertussis (non‐live) Vaccination against the highly infectious Bordetella pertussis is routine in Australian children, with a booster recommended for special risk adults including those in close contact with health care, children and infants.5 Vaccination with the diphtheria–tetanus–pertussis vaccine should be strongly considered for patients with MS who lack immunity or have not have a booster within the previous 5 years. Meningococcal disease (non‐live) Combination quadrivalent conjugate meningococcal vaccination is routine for Australian infants, children and adolescents.5 Given their chronic medical condition and immunosuppression, patients with MS treated with DMTs are recommended to receive both combination quadrivalent conjugate and non‐routine meningococcal B vaccinations.5 Further risk factors include frequent travel, individuals living in close quarters, and smoking. Yellow fever (live) Patients with MS planning travel to yellow fever endemic regions should be encouraged to think carefully about their itinerary. A small study of patients not on highly effective DMTs observed a significant increase in relapse rate following exposure to the yellow fever vaccine,11 although this was not corroborated in a recent case series.32 When yellow fever vaccination is essential, DMT cessation with a washout period is required. Given a single‐dose vaccine is protective for life, yellow fever vaccination could be offered before DMT commencement, especially if DMT initiation is delayed for other vaccinations. Concerns regarding the elevated risk of vaccine‐related adverse events in older patients should also be considered.33 When the risk of vaccination outweighs the benefits and the itinerary cannot be changed, a letter detailing why the vaccine cannot be administered should be provided. Patients should also be informed of the quarantine requirements and national policies of their destination. Human papillomavirus (non‐live) Substantial evidence suggests immunocompromise predisposes to persistent human papillomavirus (HPV) infection and related diseases, including cervical and anal cancer.34 HPV vaccination is not routinely recommended for adults, except for immunocompromised patients, and men who have sex with men.35,36 Although data on women with MS are lacking, the nonavalent HPV vaccine should be considered in non‐vaccinated adults and adolescents preparing for, or already taking, DMTs. The use of cervical HPV DNA testing to determine potential benefit from vaccination is not recommended.35,36 The Australian National Cervical Screening Program recommends immunocompromised women with a negative HPV result be re‐screened every 3 years (rather than every 5 years in immunocompetent women).35,36 Travel vaccines Patients with MS should be counselled regarding their itinerary, need to travel, and risks of infections in the context of their travel plans and prescribed DMT. As with other vaccines, non‐live vaccinations are considered safe, whereas live vaccines are contraindicated in those receiving DMTs and must be given after an appropriate washout period. Patients should be made aware that the immunogenicity of non‐live vaccines in the context of DMTs is inadequately studied. Referral to a specialised travel medicine clinic is recommended. Summary Determining immunisation status when commencing DMTs is key, as is an individualised approach to risk–benefit assessment when considering vaccinations. Live vaccinations are contraindicated in patients once they have commenced a DMT. Although we consider it safe to combine non‐live vaccinations with DMTs, data are limited regarding their efficacy and durability. Box 1 – Standard safety and immune status workup before commencing disease‐modifying therapy Varicella zoster serology (IgG) Measles serology (IgG) Mumps serology (IgG) Rubella serology (IgG) Hepatitis B (surface antibody and antigen, and core antibody) and C serology Human immunodeficiency virus serology Syphilis serology Mycobacterium tuberculosis interferon‐γ release assay* and/or chest x‐ray Travel vaccine workup if clinically appropriate Additional considerations: vaccination and infection history; cervical screening * May be affected by immunosuppressive therapies taken at the time of testing; this has been established for patients on teriflunomide and may be the case for other drugs.2 Box 2 – Summary of vaccines Vaccine type Recommendations and comments Influenza* Safe and recommended annually for patients with MS, including those on DMTs4 Varicella zoster virus† primary infection (chickenpox) Give before DMT as two doses at least 1 month apart; consider reducing interval to 2 weeks if DMT commencement is urgent5 Avoid re‐checking varicella zoster virus serology after vaccination, as failure to seroconvert may not preclude functional immunity6 Delaying DMT commencement to retest for seroconversion is also not recommended When DMT cannot be delayed or ceased, antiviral prophylaxis could be considered in high risk circumstances until a window for vaccination arises Prophylaxis could be similarly considered if a patient is inadvertently given live vaccine while receiving DMT5 Varicella zoster virus† reactivation (shingles) Give before DMT Prophylaxis could be considered if a patient is inadvertently given live vaccine while receiving DMT5 Non‐live vaccine may prove useful to patients taking DMTs in future but is currently in global short supply7 Measles–mumps–rubella† Give before DMT in vaccine‐ and infection‐naïve patients — recommended as two doses, at least 1 month apart5 Recommended for women considering future pregnancy, if no evidence of immunity before DMT commencement Patients who lose serological immunity despite exposure or single‐dose vaccination may benefit from single‐dose revaccination8 Patients unable to receive vaccine require education about post‐exposure management Pneumococcus* Adults should be offered a single dose with a follow‐up dose after 5 years The multidose schedule should be particularly applied to patients receiving B cell‐depleting agents, or after immune‐ablative therapies. In adults without a history of pneumococcal vaccination, the preferred order is one dose of 13vPCV followed by a dose of 23vPPV 8 weeks later; if 23vPPV is administered first, then 13vPCV should be administered 1 year later5 Hepatitis B virus* Recommended for patients with MS, who generally fit at‐risk category owing to their chronic condition and immune status Three‐dose schedule at months 0, 1 and 6; where possible, first dose should be given before commencement of any DMT Some flexibility between dosing is permissible: minimal interval between doses 1 and 2 is 1 month; minimum of 2 months between doses 2 and 3; and 4 months between doses 1 and 35 Serological response should be measured and specialist advice sought for vaccine non‐responders Specialist referral before DMT commencement is required for patients with serological evidence of prior or chronic infection Diphtheria–tetanus–pertussis* Vaccination recommended for patients with MS lacking immunity; consider booster before DMT commencement Adults who sustain deep and/or dirty wounds and have not received the vaccine within the previous 5 years should be revaccinated with either diphtheria–tetanus–pertussis or diphtheria–tetanus vaccine5 Vaccination should not be delayed even in patients experiencing an active relapse, as the benefits are thought to outweigh the risks9 In addition, tetanus immunoglobulin is recommended for patients with defective humoral immunity (eg, anti‐CD20 therapy) who sustain such wounds Meningococcus* Patients with MS treated with DMTs are recommended to have both routine combination quadrivalent conjugate and non‐routine meningococcal B vaccinations Also recommended if close contact with laboratories, health care and young children has occurred Close contacts of meningococcal cases should also be considered for post‐exposure prophylaxis with vaccination5 Human papillomavirus* In Australia, vaccination at 12–13 years of age is routine for both females and males; those aged ≤ 19 years are eligible for a government‐funded vaccine, while older patients may need to self‐fund Three doses spaced at 0, 2, and 6 months for people > 15 years (two‐dose schedule for non‐immunocompromised aged under 14 years) Vaccination should be considered in DMT‐exposed, non‐vaccinated adults and adolescents Additional considerations for special groups Travel vaccines: yellow fever†, hepatitis A virus*, typhoid (oral† and intramuscular* vaccines), Japanese encephalitis†, rabies*, cholera†, polio (oral† and intramuscular* vaccines), tuberculosis (bacille Calmette–Guérin vaccine)†, dengue* (not yet available) Q fever* vaccine for people working in abattoirs 13vPCV = 13‐valent pneumococcal conjugate vaccine; 23vPPV = 23‐valent pneumococcal polysaccharide vaccine; DMT = disease‐modifying therapy; MS = multiple sclerosis. * Non‐live vaccine: safe with DMTs but immunogenicity not conclusively established. † Live vaccine: contraindicated with DMTs. Box 3 – Vaccine safety and efficacy with disease‐modifying therapies Disease‐modifying therapy Recommendations Vaccine use in clinical trials Corticosteroids Generally used to accelerate recovery in the setting of a relapse (eg, 3–5 days). Guidelines suggest avoiding vaccinations during clinical multiple sclerosis relapses.9,12 Low dose corticosteroids (< 20 mg/day): safe to give vaccinations.5 Higher dose steroids > 20 mg/day used for < 14 days: give live vaccines 1 month before or any time after treatment;5 some experts recommend waiting 2 weeks after higher dose steroids before giving live vaccines.16 Higher dose steroids used for > 14 days: wait 1 month before live vaccine use. Non‐live vaccines are safe. Teriflunomide Clinical trials and post marketing data suggest non‐live vaccinations are safe and effective during treatment.17 Live vaccines should be avoided during therapy and be given after a washout period of at least 6 months due to prolonged effects on the immune system. Although accelerated washout can be achieved using cholestyramine or activated charcoal, there are no data regarding earlier use of live vaccinations following this. Seasonal influenza vaccine was found to be safe and efficacious.18 A double‐blind placebo‐controlled study evaluated immune responses to a neoantigen (rabies) and recall antigens in healthy subjects treated with teriflunomide. The treatment group achieved seroprotective levels against rabies, albeit at reduced levels compared with the placebo group. Recall antigens were not affected, suggesting no adverse effect on cellular memory response.17Teriflunomide impairs tuberculosis interferon‐γ release assay, which should be cautiously interpreted in this setting.2 Dimethyl fumarate Clinical trials and post marketing data suggest non‐live vaccinations are safe and effective during treatment.19 Use of live vaccinations is not recommended during treatment. If required, the final live vaccine dose should be given 4–6 weeks before the commencement or recommencement of treatment. An open label multicentre study evaluated immune response to tetanus, diphtheria, polyvalent pneumococcal vaccine, and meningococcal conjugate vaccines in patients receiving dimethyl fumarate or interferon. Serological evidence consistent with protection for all vaccines was comparable between the two groups, with no safety concerns raised.19 Fingolimod Clinical trials and post marketing surveillance data suggest that non‐live vaccinations are safe with fingolimod, albeit with impaired efficacy. The use of live vaccinations is not recommended during treatment. A washout period of 2–3 months is recommended to enable immune reconstitution. There are no data to support the use of lymphocyte counts as a marker of immune reconstitution for vaccine safety. The commencement or recommencement of fingolimod should be delayed until 4–6 weeks after the final vaccine dose. Fingolimod has also been associated with infection‐associated malignancies such as cervical cancer. Careful observance of screening programs is recommended. A blinded randomised placebo‐controlled study evaluated vaccination response in 138 fingolimod‐treated patients. The response rates for novel antigen influenza vaccine (fingolimod v placebo) were 54% and 85%, respectively, at 3 weeks, and 43% and 75%, respectively, at 6 weeks after vaccination. For tetanus toxoid, response rates were 40% and 61%, respectively, at 3 weeks, and 38% and 49%, respectively, at 6 weeks after vaccination. The authors concluded that, despite reduced vaccine response, patients remained capable of producing antibody levels consistent with protection.20 Cladribine Use of live vaccinations is not recommended during treatment, and treatment should not be initiated within 4–6 weeks after live vaccinations. The manufacturer recommends against live vaccination during or after a treatment, until white blood cell counts have normalised.21 Data regarding safety or efficacy of vaccines following treatment are lacking. Live vaccines were prohibited in the placebo‐controlled CLARITY trial.22 Several patients were exposed to non‐live vaccinations with no adverse events reported. The optimal timing of vaccination with regard to treatment, and the impact of cladribine therapy on vaccine efficacy, are not known. Natalizumab Clinical trials and post marketing surveillance data suggest that non‐live vaccinations are safe and effective during treatment. The use of live vaccinations is not recommended during therapy. A phase 4, open label, randomised study measured response to tetanus in natalizumab‐treated patients, all of whom achieved protective levels of tetanus antibodies.23 A study found no statistically significant difference in mean influenza IgG levels between patients receiving natalizumab and healthy controls following vaccination, suggesting maintained humoral immune response.24A study observed reduced long term protection after H1N1 influenza vaccination in natalizumab‐treated patients; the authors suggested the need for two vaccine doses in the setting of an influenza pandemic.4 Alemtuzumab Alemtuzumab treatment should be delayed for 6 weeks following the final dose of a live vaccine. The efficacy of non‐live vaccines during or after alemtuzumab therapy for multiple sclerosis is unclear. One study suggests patients are able to maintain viral immunity following treatment. Data regarding the safety of live vaccines following immune reconstitution are also lacking; this may in theory be safe, especially if T and B cell subsets have normalised. A case–control study observed preserved serological response to diphtheria, tetanus, polio, Haemophilus influenzae, meningococcal C and pneumococcus vaccines in alemtuzumab‐treated patients.25 Pre and post alemtuzumab antibody levels to common viruses (measles–mumps–rubella, varicella zoster and Epstein–Barr) were comparable with historical controls, suggesting pre‐existing immunity does not decline after treatment.25 Data from alemtuzumab used for rheumatoid arthritis suggests that vaccine response to both neoantigens and recall antigens returns to normal and remains normal up to 20 years.26 Ocrelizumab, rituximab Vaccine response in patients receiving anti‐CD20 agents may be attenuated.27 It is therefore recommended that all necessary vaccines be completed before anti‐CD20 treatment. Anti‐CD20 therapy should be delayed for 4–6 weeks following the final dose of a live vaccine. The safety of immunisation with live vaccines following ocrelizumab has not been studied and it is therefore not recommended during treatment and until B cell repletion (which may take up to 72 weeks).28 Ocrelizumab exposure during pregnancy may result in neonatal B cell depletion, which may impact the safety and efficacy of neonatal vaccinations. Monitoring of neonatal CD19 counts is recommended, and vaccines should be administered only after normalisation.28 Following treatment for over 2 years, the proportion of patients with positive antibody titres against pneumococcus, measles–mumps–rubella and varicella zoster virus were similar to baseline, suggesting CD20 B cell depletion does not impact pre‐existing protective viral antibodies.28 A randomised controlled trial investigated the impact of ocrelizumab therapy on response to tetanus, influenza and pneumococcus vaccines. An adequate vaccine response was mounted by all patients but was attenuated in the ocrelizumab group relative to the control group.27

Cassie Nesbitt · Louise Rath · Michael Zhong · Allen C Cheng · Helmut Butzkueven · Robb Wesselingh · Olga Skibina · Mastura Monif · Wei Yeh · Julia ML Brotherton · Stephen Reddel · Anneke Van Der Walt

A multilayered action plan is needed for a substantial, timely and sustained investment in dementia prevention In 2012, the Australian Government declared dementia as the ninth National Health Priority Area. Eight years later, dementia is the greatest cause of disability in Australians aged over 65 years, the second leading cause of mortality, and the highest in women.1 Today, more than 459 000 Australians live with dementia, and this number is expected to exceed one million by 2056.2 The societal, economic and health care burden of dementia is unprecedented, with significant impacts on individuals, caregivers and families. In addition to therapeutic advances, improved and timely diagnosis and coordinated person‐centred care, dementia prevention and risk‐factor management are our best chance to make a difference.3 How do we tackle dementia prevention cost‐effectively in the post‐pandemic era? Between 40% and 48% of dementia risk is considered modifiable.4,5 In Australia, the population‐attributable risk of dementia risk factors, in descending order, are physical inactivity (17.9%), mid‐life obesity (17.0%), low educational attainment in early life (14.7%), mid‐life hypertension (13.7%), depression (8.0%), smoking (4.3%), and diabetes mellitus (2.4%).5 In addition, the 2020 Lancet Commission report on dementia prevention, intervention and care4 includes hearing loss, traumatic brain injury, alcohol use, social isolation, and air pollution as risk factors. Emerging research suggests that a suboptimal diet,6 cognitive inactivity7 and sleep–wake disturbance8 also influence the modifiable dementia risk. We urge substantial, timely, and sustained investment in dementia prevention via a multilayered action plan with eight recommendations (Box). 1. Create public health and clinical practice guidelines for dementia prevention across the lifespan for the Australian setting. In 2019, the World Health Organization released dementia risk‐reduction guidelines stating that “the existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach”.9 These guidelines focus on “interventions that delay or slow cognitive decline or dementia,” with the strongest recommendations being applied to addressing physical inactivity, tobacco cessation, hypertension and diabetes mellitus.9 Yet, in Australia, we do not have dementia prevention guidelines, with the clinical practice guidelines for dementia from the National Health and Medical Research Council (NHMRC) and the Australian Cognitive Decline Partnership Centre (CDPC) focusing on diagnosis and management.10 Since then, Australia has made significant progress by including dementia prevention guidelines for general practitioners in the CDPC’s Care guide for general practice.11 We recommend extending guidelines beyond primary care, including secondary prevention in memory clinics, prioritising educational attainment in early life, and developing occupational and environmental policy to reduce hearing loss, traumatic brain injury, and air pollution. 2. Equip and resource primary care providers to be the clinical spearheads for dementia prevention throughout life. Primary care is the usual entry point and key coordinator of care within the health care system and is well positioned to spearhead dementia prevention throughout life. The Medicare Benefits Schedule should increase focus on dementia prevention, enabling primary care, specialists, and allied health professionals more time, resources and team care. This could be achieved through new Medicare Benefits Schedule item numbers and modification of existing items, such as the 45–49‐year‐old health check for individuals at risk of chronic conditions. Private health insurers could complement this by expanding the scope of preventive health services to target dementia risk factors and rewarding individuals who participate with lower insurance premiums or greater rebates for health services. 3. Support multidisciplinary memory clinics and specialists to implement secondary prevention programs for those at high risk. Memory clinics and specialists should focus on secondary prevention for people at higher risk, such as those with mild cognitive impairment.12 The Australian Dementia Network (ADNeT) aims to unite and build the network of memory clinics, establish practice guidelines, harmonise assessments, and implement dementia prevention tools and strategies. ADNeT will also facilitate access to clinical trials, improve diagnostic accuracy to aid secondary prevention approaches and introduce a Clinical Quality Registry. 4. Fund research for evidence‐based interventions for modifiable risk factors for dementia across the life cycle to reduce the evidence‐to‐practice gap. While there has been increasing funding for dementia prevention research and the establishment of the International Research Network on Dementia Prevention as part of the Australian Government’s commitment to the World Dementia Council,13 urgent funding is still required to address critical evidence‐to‐practice gaps. The current evidence base includes observational studies and intervention trials that have generally focused on cognitive outcomes, rather than dementia incidence, given the long time frames needed. We need to strengthen the evidence base on managing risk factors across different phases of the lifespan, such as the most effective doses and forms of interventions in large‐scale trials. Rigorously evaluated multidomain prevention trials that simultaneously target multiple risk factors may present the best value for money if shown to be effective and sustainable, particularly as they address risk factors that have an established evidence base for preventing other conditions. A number of these trials are already underway in Australia. 5. Implement findings from dementia risk reduction and implementation research through translation into health promotion programs. Implementation research will be key to translating the increasing evidence base for dementia risk reduction interventions into effective health promotion programs. The science of behaviour change will be critical given the evidence‐to‐practice gap. This emphasises the importance of co‐design to empower individuals to modify their risk. For health professionals, education and training on dementia risk factors and skills in motivational interviewing and behaviour change principles should be prioritised. 6. Strengthen dementia prevention public health campaigns embracing Australians’ diversity, particularly Aboriginal and Torres Strait Islander Australians. Australian‐specific dementia prevention guidelines that inform public health campaigns need to appeal to all Australians, embracing geographic, socio‐economic, cultural, linguistic, social, ethnic, age, gender, and sexual diversity. This is particularly important for Aboriginal and Torres Strait Islander people, for whom dementia prevalence is three to five times higher than the general population. These measures need to be equitable and not disadvantage vulnerable groups that may already have reduced access to resources. 7. Resource and coordinate a whole‐of-community approach including government, public and private health care, community services and education sectors to operationalise guidelines and multifaceted dementia prevention programs throughout life. Dementia prevention is everyone’s business. Successful public health and disease prevention campaigns have required a coordinated effort across all levels of the health sector, government, policy makers, non‐government organisations, research, education, industry and the community. Yet, many Australians do not believe that dementia risk can be reduced.14 Dementia prevention is complex due to stigma, literacy, and multifactor risks throughout life. The success of widely known public health campaigns in Australia (eg, Quit for Life and Slip, Slop, Slap) is attributable to their focus on behaviour change using a single behaviour or risk factor, informed by knowledge of barriers and enablers. The Dementia Australia Your Brain Matters campaign was targeted at raising public awareness for dementia, but this was not sustained beyond the funding period (2012–2015). The report from the Lancet Commission identifies educational attainment in early life as an impactful risk factor4 and this should be prioritised given its broader socio‐economic benefits. There are specific mid‐life (hearing loss, traumatic brain injury, hypertension, alcohol intake, obesity) and late‐life factors (smoking, depression, social isolation, physical inactivity, diabetes, air pollution) which offer opportunities for risk reduction across the lifespan.4 From a practical perspective, as many dementia risk factors are shared with other chronic conditions, particularly vascular risk factors, these may present the best opportunity for greatest impact. 8. Mobilise peak health advocacy bodies to promote and coordinate public health messaging on dementia risk factors that cut across chronic conditions. How do we ensure value for money and sustainability of dementia prevention public health campaigns? A unified approach with clear messaging communicated through media, community organisations, and health professionals promoting shared responsibility is crucial. An initial focus on risk factors with the highest population‐attributable risk (physical inactivity and midlife obesity) is recommended to improve wellbeing and reduce risk for multiple chronic conditions. They are also ideal for integrated programs given their overlap with vascular risk factors and successful campaigns (eg, smoking cessation). A key step is the coordination and pooling of resources between peak advocacy bodies such as Dementia Australia, Diabetes Australia, and the Heart Foundation, with clear messaging focusing on single risk factors that have multiple benefits. In clinical practice, this facilitates approaches that are tailored to an individual’s experiences and motivation. For example, motivation for increasing physical activity for one individual may arise from receiving a result of impaired glucose tolerance, while for another it may be the experience of having a family member living with heart disease or dementia. Australia has excellent health infrastructure and an international reputation for dementia prevention due to our depth of clinical, research, and knowledge translation expertise. If we are committed to achieving the ambitious targets of reduced dementia prevalence and incidence, we must shine a spotlight on dementia prevention across all levels of society. To achieve this, the National Health and Medical Research Council National Institute for Dementia Research (NNIDR) Dementia Prevention Special Interest Group proposes this Dementia Prevention Action Plan for Australia. It is time for a call to action in the fight against dementia: dementia prevention needs to be the next international public health area of focus, with Australia playing a leading role. Box – Dementia Prevention Action Plan

For the NHMRC National Institute for Dementia Research, Dementia Prevention Special Interest Group*