Central Clinical School Public Lecture 2022: The ageing brain and dementia, by Professor Velandai Srikanth

1. NCHA Public Lecture The ageing brain and dementia What can we do about it? Prof Terry O’Brien Head of Central Clinical School Monash University (Moderator) Prof Velandai Srikanth Director NCHA (Presenter)

3. Professor Velandai Srikanth Central Clinical School, Monash University Peninsula Health National Centre for Healthy Ageing (ncha.org.au) 25 October 2022 Why does the brain age, what causes dementia, and what can we do about it? Ngarnga Centre, Frankston Hospital, Peninsula Health

4. Why talk about brain ageing? Because it helps us understand how to maintain our brain health – to help prevent or delay the development of significant brain-related conditions as we get older Parkinson’s Disease Stroke

5. My talk today ⮚Some facts about dementia ⮚How brain ageing may become dementia ⮚Identifying people at high risk for prevention of dementia ⮚Helping people with symptoms of dementia

6. Some facts about dementia

7. Dementia touches many of us…

8. What is dementia? Progressive decline in more than one type of cognitive function With time, it begins to affect a person’s daily life Usually detected when a person begins to express symptoms can be observed or signs that can be captured birth death Time Cognition Detection threshold for dementia hig h lo w

9. Dementia – the scale of the problem (AIHW Web report Sep 2022) Estimated number of Australians living with dementia 2010-2058 In 2021 it was estimated between 386,200 and 472,000 Australians are living with dementia (More accurate estimates are needed) How do we compare with other countries?

10. How prevalent is dementia in our region (AIHW Web report Sep 2022) In 2021 it was estimated around 60,000 Melburnians are living with dementia (More accurate estimates are needed)

11. The impact of dementia (AIHW Web report Sep 2022) Second leading cause of death in Australia (first for women) Third leading cause of disease burden (first for women) • In 2021, it is estimated there are between 134,900 and 337,200 unpaid carers of people with dementia who live in the community • Half of primary carers of people with dementia were caring for their partner with dementia • 47% of primary carers of people with dementia were providing on average 60 or more hours of care every week

12. Brain changes in dementia – abnormal proteins and premature loss of neurons Masters Bush Gotz Watson Martins Rowe Neurodegeneration Lewy Bodies Amyloid Tau TDP-43

13. Brain changes in dementia – vascular injury (related to blood vessels and heart) Silent infarcts White matter lesions Microbleeds Microinfarcts Infarct Bleed Cerebrovascular Disease Srikanth Yassi Yates Moran Sachdev Brodtmann

14. Many roads to dementia – but not built in a day It is now accepted without a doubt that the majority of people who have dementia have more than one type of pathology in their brains These pathologies begin to accumulate at least for a decade or two before symptoms become evident No dementia Dementia Neurology. 2015 Aug 11; 85(6): 535–542 Dementia Cerebrovascular disease Neurodegeneration

15. The greater the burden of disease accumulation – the sooner the “expression” of dementia Neurology. 2015 Aug 11; 85(6): 535–542

16. Fact about dementia - summary ⮚ Highly prevalent and a leading burden of disease ⮚ At death, most people with dementia have a mixture of pathologies in their brains – suggesting the presence of multiple causes as the most common scenario ⮚ More the number of pathologies, the greater the impact on the brain and cognitive function – and hence earlier the expression of dementia Time Cognition Detection threshold for dementia hig h lo w birth death

17. Brain ageing and how it may turn into dementia

18. Is brain ageing synonymous with dementia? (Will everyone get dementia as they get older?)

19. What is “usual” brain ageing? (Bethlehem et al, Nature, April, 2022) Brain growth chart from ~120,000 MRI scans The brain expand quickly early in life and then shrink slowly with age Cognitive impact of “usual” brain ageing ⮚ Speed of thinking and problem solving ⮚ Complex attention (multitasking) ⮚ No impact on usual functioning

20. Why does the brain age? Oxidative stress Low grade inflammation Mitochondrial dysfunction Impaired DNA repair Impaired metabolism Neuronal dysfunction and death Vascular dysfunction Direct effects

21. What factors affect the trajectory of usual brain ageing and when? Pregnancy Childhood Young Adult Midlife Old age Diet Activity Education Diet Weight Activity Diet Weight Activity Diet/Sleep Weight Activity Diet/Sleep Smoking Alcohol & other drugs Head trauma Smoking Diabetes Hypertension Cholesterol Alcohol & other drugs Mental illness Diabetes Hypertension Atrial fibrillation Hearing impairment Social isolation Smoking Alcohol & other drugs Genes

22. Childhood fitness and obesity impact on brain ageing at midlife Childhood Determinants of Adult Health Study (1985-2019) School age children who were the fittest and leanest had the best cognitive scores at age ~40 J of Science and Medicine in Sport, 2022 25:8, 667-672

23. Diabetes at midlife accelerates brain ageing– a twin study J Diabetes Research Person with type 2 diabetes at midlife had to work harder and use more brain networks to achieve the same task as their twin without diabetes

24. Type 2 diabetes in old age linked to greater loss of brain volume Brain volume loss was linked with poorer cognitive function Diabetes Care 2013;36(12):4036–4042

25. When does “usual brain ageing” become “unusual”? Pregnancy Childhood Young Adult Midlife Old age Diet Activity Education Diet Weight Activity Diet Weight Activity Diet/Sleep Weight Activity Diet/Sleep Smoking Alcohol & other drugs Head trauma ApoE4 genotype Smoking Diabetes Hypertension Cholesterol Alcohol & other drugs Mental illness ApoE4 genotype Diabetes Hypertension Atrial fibrillation Hearing impairment Social isolation Reserve, resistance, plasticity, resilience Promote cognitive decline Smoking Alcohol & other drugs Genes Abnormal proteins Silent vascular changes Strokes Protect against cognitive decline Oxidative stress Low grade inflammation Mitochondrial dysfunction Impaired DNA repair Impaired metabolism Neuronal dysfunction and death

26. “Usual brain ageing to dementia” is a “Net-Sum Game” ⮚ Brain volume peaks early and then slowly declines ⮚ Several known (unknown) factors that either • promote brain development • provide a buffer against harm • hasten brain ageing All with small but important effects, and impacting during various stages of life ⮚ Many of these factors increase the risk of harmful protein deposition in the brain, and/or vascular lesions later in life ⮚ The expression or detection of dementia depends on the “net-sum” of all these small effects Time Cognition Detection threshold for dementia hig h lo w Low reserve, resistance, resilience High reserve, resistance, resilience birth death

27. Can we detect people at high risk and prevent (delay) dementia?

28. Prevention is about “shifting the curve” Time Cognition Detection threshold for dementia hig h lo w Low reserve, resistance, resilience High reserve, resistance, resilience birth death

29. Risk prediction for prevention (midlife to old age) – an example The CAIDE score Characteristics used – Age, sex, education, body mass index, blood pressure, cholesterol, smoking status, physical activity level. ⮚ At best moderate ability to say whether a person at midlife has either a “below average” or “above average” risk of developing a dementia 20 years later. ⮚ Not good for providing an individual clinical risk estimate ⮚ Reasonable to identify groups at relative high risk for testing preventive interventions

30. The FINGER study An intensive multifactor preventive trial ⮚ 2654 people aged 60-77y assumed at high risk by the CAIDE score ⮚ Treatment group (intensive diet, exercise, cognitive training, vascular risk monitoring) compared with a control group (general health advice) over 2 years ⮚ Beneficial in terms of preserving cognitive function ⮚ First real-world evidence showing that multiple factors require attention to slow cognitive decline in people at risk Lancet. 2015 Jun 6;385(9984):2255-63.

31. Other useful and emerging indicators of future risk Walking speed Grip strength Digital cognitive screen

32. 32 The future of dementia risk prediction and prevention Clinical Brain imaging Blood tests

33. Dementia care – the next frontier Removing the stigma in post-diagnostic care ⮚ Access to allied health and rehabilitation ⮚ Better systems of hospital care ⮚ Better access to diagnosis and management in residential care ⮚ Greater and purposeful social connections – intergenerational activity

34. What can we do to for people with symptoms of dementia?

35. Early detection is important – when do you seek help and why? Symptoms are persistent, progressive, and begins to affect your ability to carry out familiar tasks Other conditions can cause symptoms (depression, medications etc..) – these are eminently treatable Stop the worry of not knowing Help family & friends understand the reason for how you are feeling Diagnosis can assist with ⮚ Consideration of specific treatments ⮚ Linkage with services and support systems (e.g. Dementia Australia) ⮚ Support for carers ⮚ Access to trials of new treatments

36. 36 Can we change the course of the disease with medications? Amyloid protein removal therapies ⮚ Are we treating too late? ⮚ Addresses only one potential cause

37. Dementia care – the next frontier Removing the stigma in post-diagnostic care ⮚ Access to allied health and rehabilitation ⮚ Better systems of hospital care ⮚ Better access to diagnosis and management in residential care ⮚ Greater and purposeful social connections – intergenerational activity

38. NCHA Public Lecture The ageing brain and dementia What can we do about it? Q&A session Prof Terry O’Brien Head of Central Clinical School Monash University (Moderator) Prof Velandai Srikanth Director NCHA (Presenter)

39. NCHA Public Lecture The ageing brain and dementia What can we do about it? Thank you www.ncha.org.au

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Central Clinical School Public Lecture 2022: The ageing brain and dementia, by Professor Velandai Srikanth