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Down Syndrome and Alzheimer Disease April 8, 2005, Regina

Down Syndrome and Alzheimer Disease April 8, 2005, Regina. Lilian Thorpe BSc MSc MD FRCP Geriatric Psychiatrist, Saskatoon Health Region Professor (Clinical) Department of Psychiatry, University of Saskatchewan Chair, Section on Geriatric Psychiatry, Canadian Psychiatric Association.

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Down Syndrome and Alzheimer Disease April 8, 2005, Regina

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  1. Down Syndrome and Alzheimer DiseaseApril 8, 2005, Regina Lilian Thorpe BSc MSc MD FRCP Geriatric Psychiatrist, Saskatoon Health Region Professor (Clinical) Department of Psychiatry, University of Saskatchewan Chair, Section on Geriatric Psychiatry, Canadian Psychiatric Association

  2. Down Syndrome NSW, Australia http://www.dsansw.org.au/

  3. Premature aging in a 40 year old man with DS Wisniewski KE et al. Aging and AD in people with DS. IN: Down Syndrome: Advances in Medical Care. Ed Lott & McCoy Wiley-Liss 1992

  4. History of DS • First complete description of DS by Seguin, 1846 • Report by Down on “Observation on the ethnic classification of idiots” 1866 • 62 cases published by Fraser and Mitchell 1876 mentioned maternal age as a risk factor, described phenotypic description, neuropathology and noted dementia risk. • LeJeune & Jacobs determined DS was caused by trisomy 21, 1959. Korenberg JR et al. Advances in the understanding of Chromosome 21 and DS. IN: Down Syndrome: Advances in Medical Care. Ed Lott & McCoy Wiley-Liss 1992

  5. DS: Genetic Spectrum • Most have complete trisomy of chromosome 21 • Approximately 5% have only partial trisomy 21 (from translocations) • About 2% have mosaicism (some cells with trisomy 21 and some without). Nora & Fraser (Eds). Medical Genetics. Principles and Practice, 4th edition. Lea and Febiger Phuiladelphia1993

  6. Korenberg JR et al. Advances in the understanding of Chromosome 21 and DS. IN: Down Syndrome: Advances in Medical Care. Ed Lott & McCoy Wiley-Liss 1992

  7. DS Rate per 10,000 total births Health Canada. Congenital anomalies in Canada-a perinatal health report, 2002. Ottawa: Minister of Public Works and Government Services Canada, 2002. http://www.phac-aspc.gc.ca/publicat/cac-acc02/

  8. DS Rate per 10,000 total births Health Canada. Congenital anomalies in Canada-a perinatal health report, 2002. Ottawa: Minister of Public Works and Government Services Canada, 2002. http://www.phac-aspc.gc.ca/publicat/cac-acc02/

  9. Glasson, EJ et al. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clinical Genetics, Nov2002, Vol. 62 Issue 5, p390-4.

  10. The changing survival profile of people with Down's syndrome: implications for genetic counselling. • The present study was based on a continuous cohort of 1332 people with down's syndrome in western Australia, registered for intellectual disability services between 1953 and 2000. • Their life expectancy was 58.6 years, 25% lived to 62.9 years, and the oldest living person is 73 years of age. • Life expectancy for males was greater than females by 3.3 years. Glasson, EJ et al. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clinical Genetics, Nov2002, Vol. 62 Issue 5, p390-4.

  11. Glasson, EJ et al. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clinical Genetics, Nov2002, Vol. 62 Issue 5, p390-4.

  12. Glasson, EJ et al. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clinical Genetics, Nov2002, Vol. 62 Issue 5, p390-4.

  13. History of DS-Alzheimer link • Senile plaques and neurofibrillary tangles linked to DS: • Struwe 1929 • Jervis 1948 Mann DMA. Association between AD and DS: neuropathological observations. IN: Down Syndrome: Advances in Medical Care. Ed Lott & McCoy Wiley-Liss 1992

  14. History of DS-AD link • Malamud (1964) published 251 DS cases, 20 over 37, all of which had plaques and tangles. • Similar findings by: • Solitaire & Lamarche 1966 • Neumann 1967 • Haberland 1969 • Olson & Shaw 1969 • Burger & Vogel 1973 Beach TG. AD and DS: Scientific symbiosis-a historical commentary. IN: AD, DS and their relationship. Ed Berg et al. Oxford University Press 1993

  15. Comparison between adults with DS and individuals with AD • Neuropathology • Similar content, appearance and distribution of ß/A4 containing plaques and neurofibrillary tangles. Similar anatomy of neuronal loss. • Neurochemistry • Decreases in cholinergic, noradrenergic and serotinergic neurotransmitter systems • Neuropsychology • Dementia in a majority of patients in the 6th decade in DS Holtzman & Epstein .Possible causal factors in the development of AD in persons with DS. IN: AD, DS and their relationship. Ed Berg et al. Oxford University Press 1993

  16. Etiology of dementia in DS • Triplication of chromosome 21 and associates increased gene dosages • APP • SOD-1 • S100 • Altered gene expression Holtzman & Epstein .Possible causal factors in the development of AD in persons with DS. IN: AD, DS and their relationship. Ed Berg et al. Oxford University Press 1993

  17. Risk factors for dementia in DS • Increased age • ApoE ε4 (ApoE ε2 is protective) • Oxidative damage and inflammatory responses increase β amyloid plaques • Gender and IQ -inconclusive Bush A, Beall N. Am J Mental Retar 2004;109(2):83-97

  18. Head & Lott . Mechanisms involved with beta-amyloid precursor protein processing, beta-amyloid production and possible functional outcomes in DS. Current Opinion Neurology 2004;17(2):95-100

  19. Clinical Dementia in People With ID • Many diagnostic systems used • Outcome varies with diagnostic criteria used • Individuals difficult to assess because of • Floor effects • Behavioural and medical overlap • There is no one gold standard

  20. DS-Dementia Potential Confounders • Hearing and vision loss (more common in DS) • Cardiac abnormalities • Thyroid abnormalities • Immune functioning • Cancer- leukemia • Sleep apnea • Polypharmacy Dalton et al. Association between AD and DS : Clinical observations. IN: AD, DS and their relationship. Ed Berg et al. Oxford University Press 1993

  21. DS-Dementia: Longitudinal Studies • Lai & Williams 1989 • Dementia 8% in 35-49 • Dementia 55% in 50-59 • Dementia 75% in 60+ • Lai F, Williams RS.A prospective study of Alzheimer disease in Down syndrome. Arch Neurol. 1989 Aug;46(8):849-53.

  22. Percentage Prevalence of Alzheimer’s Disease in DS (Camdex) Holland et al, BJP 1998; 172:493-8

  23. Prevalence of Dementia (Percentage) in Canada by Age Group CSHA

  24. Percentage of people with DS with plaques and tangles in the brain. Mann DMA. Association between AD and DS: neuropathological observations. IN: Down Syndrome: Advances in Medical Care. Ed Lott & McCoy Wiley-Liss 1992

  25. Saskatchewan Study of Aging in Adults with Intellectual Disabilities Liilan Thorpe MD FRCP Punam Pahwa PhD Jo Nanson PhD Andrew Kirk MD Vernon Bennett MD Please note data analysis is at an interim stage

  26. Participants in the Study • All participants 360 • DS diagnosis 116 • Non-DS diagnosis 244 • Interim data analysis

  27. Age Distribution of 360 adults with Intellectual Disability in Study at Time 1Interim data analysis

  28. Interim data analysis

  29. Interim data analysis

  30. Multivariate Cox regression analysis predicting mortality, controlling for DS diagnosis, sex, age at first assessment, baseline DMR practical skills deficits and baseline DMR mood symptoms (N=360).Interim data analysis

  31. Dementia Questionnaire for Persons with Mental Retardation (DMR) • Standardized informant-based questionnaire, consisting of 50 items, which is completed by family or staff. • Higher scores indicate a higher level of pathology, and items are answered based on behaviour over the last three months. Evenhuis HM. Evaluation of a screening instrument for dementia in ageing mentally retarded persons. J Intellect Disabil Res. 1992; 36 ( Pt 4): 337-47.

  32. DMR Subscales • 1. Short-term memory • 2. Long-term memory • 3. Spatial and temporal orientation • 4. Speech • 5. Practical skills • 6. Mood • 7. Activity and interest • 8. Behavioural disturbance

  33. Interim data analysis

  34. Interim data analysis

  35. Interim data analysis

  36. Interim data analysis

  37. Interim data analysis

  38. Interim data analysis

  39. Interim data analysis

  40. Interim data analysis

  41. Interim data analysis

  42. Interim data analysis

  43. Interim data analysis

  44. Interim data analysis

  45. Interim data analysis

  46. Interim data analysis

  47. Interim data analysis

  48. Treatment of Dementia in Down Syndrome

  49. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with DS and AD--pilot study (N=27). • Non-significant (p=0.22, p=0.06, p=51)findings in favour of donepezil compared to placebo in DMR, Severe Impairment Battery, and Adaptive Behaviour Scale. • Significantly (p=0.03) worse NPI scores on donepezil compared to placebo Prasher et al. Int J Geriatr Psychiatry. 2002 Mar;17(3):270-8.

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