Down Syndrome and Alzheimer Disease

April 8, 2005, Regina

Lilian Thorpe BSc MSc MD FRCPGeriatric Psychiatrist, Saskatoon Health RegionProfessor (Clinical) Department of Psychiatry,

University of SaskatchewanChair, Section on Geriatric Psychiatry, Canadian

Psychiatric Association

Down Syndrome NSW, Australiahttp://www.dsansw.org.au/

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• 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

• 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

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 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/

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 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

• 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• 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

• 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

• 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

• 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 .Mechanisms involved with beta-amyloid precursor protein processing, beta-amyloid production and possible functional outcomes in DS.Current Opinion Neurology2004;17(2):95-100

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

DS-Dementia Potential Confounders

• Hearing and vision loss (more common in DS)

• Cardiac abnormalities

• Thyroid abnormalities

• Immune functioning

• Cancer- leukemia

• Sleep apnea

• PolypharmacyDalton 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

• 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)

0

5

10

15

20

25

30

35

40

30-39 40-49 50-59

Prevalence

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

Prevalence of Dementia (Percentage) in Canada by Age Group

8

2.4

11.1

34.5

0

5

10

15

20

25

30

35

Age Group

65+65-7475-8485+

CSHA

Percentage of people with DS with plaques and tangles in the brain.

0102030405060708090

100

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79

Age

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

Liilan Thorpe MD FRCPPunam Pahwa PhD

Jo Nanson PhDAndrew Kirk MD

Vernon Bennett MD

Please note data analysis is at an interim stage

Participants in the Study

• All participants 360• DS diagnosis 116• Non-DS diagnosis 244

• Interim data analysis

1995 1997 1999 2001

Demographics X X X X

Health problems X X X X

Medications X X X X

Life events X X X

Use of aging services X X X X

DMR X X X X

Reiss Screen X X X X

CIDD X X X X

Dyspraxia Scale (Dalton) X X X

Name-Face test (Dalton) X X X

DTMS (Dalton) X X X

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

Interim data analysis

20.00 30.00 40.00 50.00 60.00 70.00 80.00

DMRAge1

0

10

20

30

40

50

60

Mean = 42.0944Std. Dev. = 12.41493N = 360

Interim data analysis

Interim data analysis

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

P Odds of dying

Down syndrome diagnosis .006 2.532

Sex (reference: females) .018 2.411

Age (units of ten years at baseline) .000 1.931

DMR Practical skills deficits-baseline .002 1.126

DMR Mood symptoms-baseline .008 1.192

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• 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

DMR:Short-term Memory Deficits at First Assessment

012345678

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean decrease in short-term memory per year: GEE GenMod

0

0.05

0.1

0.15

0.2

0.25

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

DMR: Long-term Memory Deficits at First Assessment

0

2

4

6

8

10

12

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean decrease in long-term memory per year: GEE GenMod

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

DMR: Spatial-temporal Deficits at First Assessment

0

2

4

6

8

10

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean decrease in spatial-temporal functions per year: GEE GenMod

0

0.05

0.1

0.15

0.2

0.25

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

DMR: Speech Deficits at First Assessment

0

2

4

6

8

10

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean decrease in speech per year: GEE GenMod

0

0.02

0.04

0.06

0.08

0.1

0.12

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

DMR: Practical Skills Deficits at First Assessment

0

1

2

3

4

5

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean decrease in practical skills per year: GEE GenMod

0

0.05

0.1

0.15

0.2

0.25

0.3

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

DMR: Mood Problems at First Assessment

0

1

2

3

4

5

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean mood decrease per year: GEE GenMod

00.010.020.030.040.050.060.070.080.09

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

DMR: Apathy at First Assessment

0

1

2

3

4

5

<30 30-39 40-49 50+ <30 30-39 40-49 50+

DS Non-DS

Interim data analysis

Mean apathy decrease per year: GEE GenMod

0

0.02

0.04

0.06

0.08

0.1

0.12

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

Mean decrease in activities-interest per year: GEE GenMod

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

Age <30 Age 30-39 Age 40-49 Age 50+

Non-DS

DS

Interim data analysis

Treatment of Dementia in Down Syndrome

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.

Percentage of patients with treatment emergent side effects (Prasher)

Placebo N=14 Donepezil N=16

Fatigue 14 44

Diarrhea 21 38

Insomnia 14 25

Nausea 7 25

Vomiting 7 13

Muscle cramps 14 13

Seizures 29 6

Dizziness 14 13

Anorexia 0 19

Agitation 0 19

Low mood 0 6