Understanding Aging in Down Syndrome: Impact, Challenges, and Health Needs

1. D Growing older with Down syndrome: understanding the changing needs of people with Down syndrome as they age Tony Holland Cambridge Intellectual & Developmental Disability Research Group, Dept. of Psychiatry, University of Cambridge, Cambridge www.ciddrg.org.uk

2. Outline…. The lifetime trajectory of people with Down syndrome Changing health needs with increasing age The link between Down syndrome and dementia (Alzheimer’s disease) – a clinical and research perspective.

3. International ContextUN Convention on the Rights of People with Disabilities (UN CRPD) • Education (Article 24 UN CRPD) • Opportunity (Articles 3 & 27 UN CRPD) • Health (Article 25 UNCRPD) ‘Provide those health services needed by persons with disabilities specifically because of their disabilities, including early identification and intervention as appropriate, and services designed to minimize and prevent further disabilities, including among children and older persons.’

4. Estimated mean life expectancy Braddock et al 1996 Early 1900’s Late 1900s male female male female Gen. Pop 45 49 81 84 People with ID* 18 66 People with DS 9 50 Bittles et al 2004, 2006 (based on Australian data) • Mean life expectancy of people with Down syndrome now 60 years. • Improving at a faster rate than the typically developing population. *ID: intellectual disabilities

5. Improvements in life expectancy • Factors in the general population • Improved nutrition and living standards • Treatment of infections & of infectious diseases • Better maternity care & decreased infant mortality • Better access to health services and to new treatments • Factors specific to people with Down syndrome • Treatment of congenital disorders • Reduction in stigma • Respect for the right to treatment • On-going health monitoring (health checks)

6. Adult life… • The impact of cognitive and functional impairments and disabilities becomes of greater significance (the ability gap widens) • Changes in family and other support networks and limited opportunities once education comes to an end • Risks for specific physical and mental health problems in adult and later life

7. Some key issues…. • The importance for adult life of good health in childhood, educational opportunities, and family life (support for families, education) • The challenge of the transition to adult life, the need for on-going support and for access to opportunities and choice (national policy) • The prevention, detection and treatment of ill-health in adult life – the interface between health and social support (practice)

8. Rates of mental-ill health in adults with DS • Collacott et al 1992 Population-based study in the UK (n=371 adults with DS and 371 aged matched control group with intellectual disabilities) • Main differences • In DS higher rates of dementia (4.3% vs 0.3%) and depression (11.3% vs 4.3%) • In DS lower rates of conduct disorder (6.2% vs 20.5% p=<0.001); schizophrenia/paranoid states 1.6% vs 5.4% • No significant differences in rates of autism

9. ‘Regression’ in young adults with DS • People with DS in late teens early adult life have been described as experiencing unexplained regression (see Ghaziuddin et al 2015, Neuropsychiatric Dis & Treatment 1:941-949) • Key characteristics • May follow life stress • Gradual onset – slowing down, reduced speech with increased latency, repetitive movements and posturing, mood fluctuations, general decline, poor sleep

10. ‘Regression’ in young adults with Down syndrome • Differential diagnosis • Depression • Major mental illness • Early dementia • Physical disorder • Other • Treatment • Pharmacological • Rehabilitation • Problem • No formal trial of interventions and uncertainty as to causation

11. Ageing in people with Down’s syndrome • Questions? • Do people with Down syndrome age prematurely? Images courtesy of the UK DSA

12. Ageing in people with Down syndrome: a research journey • Observations from the early 1900’s of brain related changes similar to those first described by Alzheimer • Although life expectancy has improved still less than that found in the typically developing population • Increased risk of age-related biomarkers and age-related illnesses earlier in life • Skin changes • Sensory impairments • Menopause (endocrine) • Physical exercise and obesity • Dementia (Alzheimer’s disease)

13. Physical activity of people with DS compared to others with intellectual disabilities (ID) not due to DS 152 people with ID aged 12 to 70 years (79 people with DS) Physical activity levels were measured using an accelerometer (Actigraph GT1M) worn for 7 days Findings • No individuals with ID met current UK Government recommended levels of physical activity • People with DS engaged in significantly less physical activity than people with ID not due to DS • Levels of activity in people with DS were lower with increasing age than people with ID not due to DS Phillips AC, Holland AJ (2011) Assessment of Objectively Measured Physical Activity Levels in Individuals with Intellectual Disabilities with and without Down's Syndrome. PLoS ONE 6(12): e28618. doi:10.1371/journal.pone.0028618

14. Mitochondrial function in people with DS Using a form of imaging, magnetic resonance spectroscopy (MRS), the time taken for energy levels in muscle to recover (phosphocreatine recovery time) after physical activity was measured. People with DS had a slower recovery time than in a control group of similar age and fitness. Phillips et al (2013) Defective Mitochondrial Function In Vivo in Skeletal Muscle in Adults with Down’s Syndrome: A 31P-MRS Study. PLoS ONE, 8(12): e84031. doi:10.1371/journal.pone.0084031

15. Definition and diagnosis • Dementia is a progressive loss of cognitive and functional abilities over time, usually occurring in later life • Alzheimer’s disease is the most common cause of dementia in the general population • The importance of assessments and diagnosis • Sensory impairments • Depression • Thyroid disorder

16. Down syndrome: Neuropathological Hallmarks First reported by Struwe et al 1920

17. Age-specific risk of dementia in people with Down syndrome ♦—♦ Lai & Williams, 1989 ▴- - -▴ Visser et al., 1997 ▪—▪ Lai et al., 1999 ▪…▪ Holland et al., 1998 Schupf, N et al; BJP 2002;180:405-410

18. DS and the risk of Alzheimer’s disease – the amyloid cascade hypothesis AD ? PS1/PS2 mutations Plaques Tangles ? ? APP A42 Tau Dysfunction Cell Death Chromosome 21 APP mutations/ Down Syndrome Tau mutations (FTDP-17) ? Hardy and Selkoe (2002), Science, 5580: 353-356 Gene for APP gene located on chromosome 21 1986

19. The use of neuroimaging MRI Structure PET Amyloid What is the relationship between brain amyloid accumulation, the loss of brain tissue and the development of dementia (Alzheimer’s disease)? Landt et al, 2013

20. Expression and localisation of APP protein (green) A human stem cell model of early AD pathology in DS Yichen Shi et al Sci Transl med (2012) DOI: 10.1126/scitransimed. 3003771

21. The research journey Trisomy 21 reported by Lejeune 1959 Sequencing of Chr. 21 Hatton et al, Nature, 2000 APP gene The Amyloid Cascade Hypothesis Selkoe 1991 Pittsburgh Compound-B (PiB), Klunk et al 2004 Clinical Landt et al 2011 ? A human stem cell model of early AD pathology in DS Yichen Shi et al 2012

22. Possible future treatments acting on amyloid and/or its pathway • Β-secretase and ϒ-secretase inhibitors (reduce production of toxic Aβ) • Active and passive immunization against Aβ42 • Antibodies • Anti-inflammatory agents (NSAID) • Statins Periphery Brain Amyloid Load

23. Key points….. • Mental ill-health and emotional problems do affect people with DS in adult life including depression and anxiety – these need to be recognised and treated. • Two specific mental health risks particular to people with DS: • Unexplained regression sometimes occurring in early adult life – prevalence and aetiology uncertain • Risk of dementia due to Alzheimer’s disease – peak age of risk early 50’s • Diagnosis can be problematic • Definite history of a change in functioning and behaviour • Evidence of a change in mental state

24. What is needed… • The maintenance of good health • The living and support environment • Diet • Exercise • The detection and treatment of ill-health • Awareness • Reasonable adjustments (Equality Act, 2010) • Access to health services • Better understanding of age-related health problems specific to people with Down syndrome • Illnesses of later life • Premature ageing • The need for research

25. The context in India… • The importance of epidemiological evidence • Age-profile of people with Down syndrome • Life-expectancy and age-related morbidity and mortality and their predictors • Societal attitudes and stigma • Opportunities in adult life (support, employment, recreation etc) • Access to health promotion, health care, health screening • Data provides the basis for campaigning and for policy and service development (UN CRPD)

26. Acknowledgments • People with Down syndrome, their families and others who support them • Funders of research including the UK DSA, MRC, Alzheimer’s Research-UK • Basic scientists, clinicians and researchers For further information see the Cambridge Intellectual and Developmental Disabilities Research Group (ciddrg) website www.psychiatry.cam.ac.uk/ciddrg/ • Film ‘Together’ to celebrate world Down syndrome day and launched at the Cambridge Arts Cinema in dementia week • Research newsletters