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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

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


Down Syndrome NSW, Australia

http://www.dsansw.org.au/


Premature aging in a 40 year old man with ds
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


History of ds
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


Ds genetic spectrum
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


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


Ds rate per 10 000 total births
DS Rate per 10,000 total births Chromosome

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/


Ds rate per 10 000 total births1
DS Rate per 10,000 total births Chromosome

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/


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.


The changing survival profile of people with down s syndrome implications for genetic counselling
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.


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.


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.


History of ds alzheimer link
History of DS-Alzheimer link with Down's syndrome:

  • 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


History of ds ad link
History of DS-AD link with Down's syndrome:

  • 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


Comparison between adults with ds and individuals with ad
Comparison between adults with DS and individuals with AD with Down's syndrome:

  • 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


Etiology of dementia in ds
Etiology of dementia in DS with Down's syndrome:

  • 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


Risk factors for dementia in ds
Risk factors for dementia in DS with Down's syndrome:

  • 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


Head & Lott . with Down's syndrome:

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


Clinical dementia in people with id
Clinical Dementia in People With ID with Down's syndrome:

  • 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


Ds dementia potential confounders
DS-Dementia Potential Confounders with Down's syndrome:

  • 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


Ds dementia longitudinal studies
DS-Dementia: Longitudinal Studies with Down's syndrome:

  • 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.


Percentage prevalence of alzheimer s disease in ds camdex
Percentage Prevalence of Alzheimer’s Disease in DS (Camdex)

Holland et al, BJP 1998; 172:493-8



Percentage of people with ds with plaques and tangles in the brain
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


Saskatchewan study of aging in adults with intellectual disabilities

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


Participants in the study
Participants in the Study Disabilities

  • All participants 360

  • DS diagnosis 116

  • Non-DS diagnosis 244

  • Interim data analysis


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


Interim data analysis in Study at Time 1


Interim data analysis in Study at Time 1


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


Dementia questionnaire for persons with mental retardation dmr
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.


Dmr subscales
DMR Subscales (DMR)

  • 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


















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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