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Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia: clinical cohort study

  • Nicole Eady (a1), Rory Sheehan (a1), Khadija Rantell (a2), Amanda Sinai (a1), Jane Bernal (a3), Ingrid Bohnen (a4), Simon Bonell (a5), Ken Courtenay (a6), Karen Dodd (a7), Dina Gazizova (a8), Angela Hassiotis (a1), Richard Hillier (a9), Judith McBrien (a10), Kamalika Mukherji (a11), Asim Naeem (a12), Natalia Perez-Achiaga (a13), Vijaya Sharma (a11), David Thomas (a14), Zuzana Walker (a1), Jane McCarthy (a15) and André Strydom (a16)...

Abstract

Background

There is little evidence to guide pharmacological treatment in adults with Down syndrome and Alzheimer's disease.

Aims

To investigate the effect of cholinesterase inhibitors or memantine on survival and function in adults with Down syndrome and Alzheimer's disease.

Method

This was a naturalistic longitudinal follow-up of a clinical cohort of 310 people with Down syndrome diagnosed with Alzheimer's disease collected from specialist community services in England.

Results

Median survival time (5.59 years, 95% CI 4.67–6.67) for those on medication (n = 145, mainly cholinesterase inhibitors) was significantly greater than for those not prescribed medication (n = 165) (3.45 years, 95% CI 2.91–4.13, log-rank test P<0.001). Sequential assessments demonstrated an early effect in maintaining cognitive function.

Conclusions

Cholinesterase inhibitors appear to offer benefit for people with Down syndrome and Alzheimer's disease that is comparable with sporadic Alzheimer's disease; a trial to test the effect of earlier treatment (prodromal Alzheimer's disease) in Down syndrome may be indicated.

Declaration of interest

A.S. has undertaken consulting for Ono Pharmaceuticals, outside the submitted work. Z.W. has received a consultancy fee and grant from GE Healthcare, outside the submitted work.

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Copyright

Corresponding author

Correspondence: Rory Sheehan, Division of Psychiatry, University College London, 6th Floor Maple House, 149 Tottenham Court Road, London W1T 7NF. Email: r.sheehan@ucl.ac.uk

Footnotes

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*

These authors contributed equally to this work.

These authors are joint last authors.

Footnotes

References

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9 Hanney, M, Prasher, V, Williams, N, Jones, EL, Aarsland, D, Corbett, A, et al. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379: 528–36.
10 Sheehan, R, Sinai, A, Bass, N, Blatchford, P, Bohnen, I, Bonell, S, et al. Dementia diagnostic criteria in Down syndrome. Int J Geriatr Psychiatry 2015; 30: 857–63.
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22 Zhu, CW, Livote, EE, Scarmeas, N, Albert, M, Brandt, J, Blacker, D, et al. Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer's disease. Alzheimers Dement 2013; 9: 733–40.
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25 Nordström, P, Religa, D, Wimo, A, Winblad, B, Eriksdotter, M. The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer's disease. Eur Heart J 2013; 34: 2585–91.
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27 Lott, IT, Osann, K, Doran, E, Nelson, L. Down syndrome and Alzheimer disease: response to donepezil. Arch Neurol 2002; 59: 1133–6.
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30 Prasher, V, Sachdeva, N, Adams, C, Haque, M. Rivastigmine transdermal patches in the treatment of dementia in Alzheimer's disease in adults with Down syndrome-pilot study. Int J Geriatr Psychiatry 2013; 28: 219–20.
31 Atri, A, Hendrix, SB, Pejović, V, Hofbauer, RK, Edwards, J, Molinuevo, JL, et al. Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis. Alzheimers Res Ther 2015; 7: 28.
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34 Dubois, B, Chupin, M, Hampel, H, Lista, S, Cavedo, E, Croisile, B, et al. Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease. Alzheimers Dement 2015; 11: 1041–9.
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Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia: clinical cohort study

  • Nicole Eady (a1), Rory Sheehan (a1), Khadija Rantell (a2), Amanda Sinai (a1), Jane Bernal (a3), Ingrid Bohnen (a4), Simon Bonell (a5), Ken Courtenay (a6), Karen Dodd (a7), Dina Gazizova (a8), Angela Hassiotis (a1), Richard Hillier (a9), Judith McBrien (a10), Kamalika Mukherji (a11), Asim Naeem (a12), Natalia Perez-Achiaga (a13), Vijaya Sharma (a11), David Thomas (a14), Zuzana Walker (a1), Jane McCarthy (a15) and André Strydom (a16)...
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eLetters

Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia

David Smith, Physician , Down Syndrome Clinic of Wisconsin
Brian Chicoine, MD, Physician
12 July 2018

As practicing clinicians who provide care to adults with Down syndrome, we appreciate the authors’ attempt to address a real concern in this patient population. However, we have significant concerns about clinicians potentially using in their practice the conclusions drawn by the authors. The study conclusions offer false hope and may result in wasted resources.

The authors themselves state that the treated and untreated groups have significant differences that would favor the treated group: “There were significant baseline differences between the groups prescribed and not prescribed antidementia medication. Those who were not prescribed medication were older, more likely to have severe–profound intellectual disability, and had more severe dementia symptoms at baseline.” Given those differences, it’s difficult to understand how the authors can come to the conclusion that treatment with anti-dementia medications is of benefit.

Also of concern is the question of what the clinical significance would be from a functional perspective. Dementia takes a tremendous toll on the caregivers and families. Even if the medications do extend life, where is the benefit? What kind of life will they have? We believe quality of life would have been a more useful measured outcome.

Furthermore, there are four published studies and Cochrane reviews that show no benefit with donepezil¹, rivastigmine², memantine3, 4, or galantamine.5 Another Cochrane Review in 2015 showed no benefit of pharmacological interventions for cognitive decline in people with Down syndrome.6

In our experience as the directors of Down Syndrome clinics for adults, the big issue is really how the diagnosis of dementia is made. Clinicians tend to easily apply the diagnosis of Alzheimer’s dementia without looking at all the potential causes of pseudodementia in this population.7 They often assume that loss of ability is due to dementia because of a study published in 1985 that showed plaques and tangles in the brain tissue of all people with Down syndrome over the age of 35 8. Wisniewski and Rabe subsequently wrote that there was a discrepancy between neuropathology and the occurrence of dementia in people with Down syndrome9. Just as in the population of typically developed older adults, the diagnosis of Alzheimer’s dementia in people with Down syndrome should be made only after evaluation for causes of pseudodementia.

Conflict of interest: None

David S. Smith, MD

Program Director, Down Syndrome Clinic of Wisconsin

Children’s Specialty Group

Children’s Hospital of Wisconsin

Associate Clinical Professor of Pediatrics

Department of Pediatrics

Medical College of Wisconsin, Milwaukee, WI USA

Brian Chicoine, MD

Medical Director

Advocate Medical Group Adult Down Syndrome Center 

Faculty

Advocate Lutheran General Hospital Family Medicine Residency

Park Ridge, IL, USA

REFERENCES

1 Mohan, M, Carpenter, PK, Bennett, C. Donepezil for dementia in people with Down syndrome. Cochrane Database Syst Rev 2009.

2 Mohan, M, Bennett, C, Carpenter, PK. Rivastigmine for dementia in people with Down syndrome. Cochrane Database Syst Rev 2009.

3 McShane, R, Areosa Sastre, A, Minakaran, N. Memantine for dementia. Cochrane Database Syst Rev 2006;

4 Hanney, M, Prasher, V, Williams, N, Jones, EL, Aarsland, D, Corbett, A, et al. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379: 528–36.

5 Mohan, M, Bennett, C, Carpenter, PK. Galantamine for dementia in people with Down syndrome. Cochrane Database Syst Rev 2009

6 Livingstone N1, Hanratty J, McShane R, Macdonald G. Pharmacological interventions for cognitive decline in people with Down syndrome. Cochrane Database Syst Rev. 2015 Oct 29;(10)

7 Chicoine B, McGuire D, Hebein S, Gilly D. Ment Retard. 1994 Apr;32(2):100-6.

Development of a clinic for adults with Down syndrome.

8 Wisniewski KE, Wisniewski HM, Wen GY, Ann Neurol. 1985 Mar;17(3):278-82.

Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome.

9 Wisniewski HM, Rabe A. Ann N Y Acad Sci. 1986;477:247-60.

Discrepancy between Alzheimer-type neuropathology and dementia in persons with Down's syndrome.
... More

Conflict of interest: None declared

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A request for clarifications and additional data

Sue Buckley, Psychologist, Down Syndrome Education International and University of Portsmouth
08 March 2018

While I congratulate this team on their attempt to explore the important issue of treatment outcomes for individuals with Down syndrome and dementia and the considerable effort that has gone into collating this data, I am concerned about the way some of the data is presented and is used to support the conclusions drawn in this article. I would like to request some clarifications and additional data.

Increased survival on drug treatment

1. The abstract states a difference in mean survival of 5.59 v 3.45 years for treated versus untreated groups but as far as I can see these figures are not adjusted for the fact the ‘no treatment’ group are older at time of diagnosis (means 56.66 v 53.81 years, similar SDs) and have significantly higher DLD scores ‘indicating that this group had more severe symptoms of dementia at diagnosis’ (p 156). It would be informative to know the means and standard deviations for actual age at death of both groups.

2. The Kaplan- Meier survival curves (Fig 1 p 157) do not seem to take into account the age differences between the groups at diagnosis and in my view are therefore misleading.

3. The Cox regression calculations of hazard ratios reported, suggesting that treatment extends survival, do not include any control for the individual variations in the extent of the progression of the disease in the analyses. The paper states that the authors have DLD scores and clinician's stage assessments (early, middle, late, p 156) at diagnosis and these differ between the drug treatment/no treatment groups. While these measures are estimates of disease progression at best, why was one of them not used as well as age at diagnosis as a covariate? Without any control for differences in disease progression I do not think the strong claim of a survival benefit for treatment can be substantiated.

Short term benefits of treatment

4. There are no benefits evident on DLD social scores and the benefits (slowing of decline) on DLD cognitive scores at 6 months are lost at 12 months. In my view, this should have been made explicit in the abstract and discussed more fully in the paper.

5. I am aware that this pattern of ‘benefit’ is similar in patients with AD in the general population but for individuals with an intellectual disability a slowing of cognitive decline followed by a more rapid decline as indicated by these data may be more difficult for them to cope with. It would be informative to see the actual means and standard deviations for the DLD measures at the 6 month and 12 month points. I also understand a more rapid decline is experienced when these drugs are stopped.

Abstracts

6. Authors, reviewers and publishers need to recognise that many people searching for information will not read beyond the abstract and take care to ensure it is a fully accurate summary when publishing findings and their implications.

Professor Sue Buckley OBE

CPsychol AFBPsS

Director for Science and Research

Down Syndrome Education International

Emeritus Professor of Developmental Disability

Dept Psychology, University of Portsmouth, UK.

... More

Conflict of interest: None declared

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