Title: Pharmacological interventions for cognitive decline in people with Downs syndrome
Funder: Department of Health (England)

Abstract: Research Question: What is the effectiveness of pharmacological interventions for cognitive decline in people with Down’s syndrome? 1.Intervention: Any pharmacological intervention that slows progression or treats cognitive decline in people with Down’s syndrome.2.Patient group: Adults with Down’s syndrome and early cognitive decline or dementia - exact inclusion criteria to be specified by applicants.3.Setting: Any.4.Control / Comparator: Placebo or another appropriate control / comparator.5.Study design: Evidence synthesis of the best available evidence. Indirect treatment comparisons can be included if data exist. Results for different groups of pharmacological intervention should be reported separately. Subgroup analysis (for example for patients with and without a diagnosis of dementia) should be carried out if appropriate. 6.Important outcomes: Decline in cognitive behavioural psychological and global functioning; carer burden. Other outcomes: Adverse effects; health related quality of life; independence; research recommendations for new primary research on the most promising interventions. NHS decision problem to be addressed by this research: Down’s syndrome is one of the most common genetic syndromes seen in clinical practice. People with Down’s syndrome have an increased risk of developing dementia as they age than others and develop it at a younger age. When people with Downs syndrome develop dementia it is usually due to Alzheimer’s disease. The comorbid picture of Down’s syndrome and dementia presents a unique challenge to the clinician in both diagnosis and management. Whilst pharmacological treatments have been shown to improve cognitive function in older adults with Alzheimer’s disease in the general population there appears to be very little evidence to support treatment of people with Down’s syndrome and dementia despite being recommended by NICE. A series of Cochrane reviews from 2009 that used strict inclusion criteria requiring a diagnosis of dementia and Down’s syndrome separately examined the four pharmacological treatments for dementia recommended by NICE in people with Down’s syndrome. Only one of the reviews found any studies to include. Since then several trials have examined pharmacological treatments for cognitive function (not necessarily requiring a diagnosis of dementia) in people with Down’s syndrome. An evidence synthesis is required that builds on and broadens previous reviews in order to clarify the current position regarding pharmacological interventions for cognitive decline in people with Down’s syndrome and to suggest future priorities for primary research in this area. Source of the topicThis topic was suggested by Professor Paul Willner member of the MPOH panel.Patient group •Down’s syndrome is one of the most common genetic disorders. It is characterised by intellectual difficulty dysmorphic facial features and a host of structural abnormalities. A recent meta-analysis reported the population prevalence of Down’s syndrome in England and Wales1: an estimated 37090 people had Downs syndrome a population prevalence of 0.66 per 1000 people; 650 under 1 2673 aged 1-5 7115 aged 5-18 12819 aged 19-40 10626 aged 41-55 and 3207 aged 56 and older. The study states that owing to sudden increases in the survival of babies with Downs syndrome in the 1950s there are a large proportion of people with Downs syndrome who are in their 40s. These people have an increased risk of developing dementia in the future and services should be aware of their potential needs. •It has been estimated that more than 40% of people with Down’s syndrome in the UK are aged 40 years or older. Over the age of 40 people with Down’s syndrome without clinically detectable dementia are said to experience an average decline of 11% on neuropsychological measures of attention executive function and memory over 1 year. Regarding actual prevalence figures for Alzheimer’s disease in people with Down’s syndrome estimates suggest that in their 40s approximately 1 in 10 of these individuals develops Alzheimer’s disease; in their 50s approximately 1 in 3 and in their 60s the figure is more than half (Epidemiological information from the Cochrane reviews). This cognitive decline is very distressing for parents and family carers resulting in high caregiver burden. •When people with Down’s syndrome develop dementia it is usually due to Alzheimer’s disease; however there is apparently growing awareness that people with Down’s syndrome can develop other forms of dementia. The diagnosis of Alzheimer’s disease or another type of dementia is not straightforward because of an absence of validated approaches for people with intellectual disabilities – for this reason the proposed patient group in this vignette does not require a formal diagnosis of dementia.•Although almost all people with Downs syndrome develop the changes in the brain associated with Alzheimers disease as they get older not all develop the symptoms of dementia. The reason for this has not been fully identified. However it is known that the protein that causes brain cell damage in Alzheimers disease is produced from a gene on chromosome 21. People with Downs syndrome have an extra copy of this chromosome which may largely explain their increased risk of developing Alzheimers disease. In people with Down’s syndrome changes in overall function personality and behaviour may be more common early signs of Alzheimers than memory loss and forgetfulness (Sources: 1 Cochrane reviews and alzheimers.org).NICE and other guidanceNICE CG42 Dementia - Supporting people with dementia and their carers in health and social care. November 2006 (revised March 2011)People with a learning disability•Only specialists in the care of patients with dementia (that is psychiatrists including those specialising in learning disability neurologists and physicians specialising in the care of older people) should initiate treatment. Carers’ views on the patient’s condition at baseline should be sought.•People in the moderate stages of Alzheimer’s disease may be given treatment with “anti-dementia” acetylcholinesterase (AChE) inhibitors donepezil (Aricept) galantamine (Reminyl) or rivastigmine (Exelon) and this includes individuals with dementia and learning disabilities.•Memantine is recommended as an option for managing Alzheimer’s disease for people with moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE inhibitors or severe Alzheimer’s disease.Proposed intervention and current practice•Any pharmacological interventions for treating cognitive decline in people with Down’s syndrome would be suitable for inclusion in the proposed evidence synthesis.•As well as presenting with dementia at a much younger age than the general population people with Down’s syndrome have subtle differences in physiology (e.g. metabolism and heart rate) that may lead to different requirements in terms of pharmacological treatment compared to the general population. It is important therefore for research to examine whether treatments shown to have some benefit for people with dementia in the general population also provide benefit for people with Down’s syndrome and dementia. •Acetylcholine is a chemical found in the brain that has an important role in memory attention reason and language. Donepezil rivastigmine and galantamine (AChE inhibitors) are all thought to maintain or increase levels of acetylcholine and are reported to have some benefits for people with mild to moderate Alzheimer’s disease in the general population. Donepezil and rivastigmine have both been investigated in people with Down’s syndrome and dementia. Importantly these AChE inhibitors are approved by NICE to treat dementia in people with Down’s syndrome despite the very limited evidence of effect.•An increase in L-glutamate is thought to contribute to the pathogenesis of Alzheimer’s disease and memantine is thought to reduce abnormal activation of glutamate neurotransmission. Memantine has been shown to improve cognitive function and slow the decline of moderate to severe Alzheimer’s disease in the general population and has been investigated in the largest RCT to date examining people with Down’s syndrome and dementia – the MEADOWS trial (see below).•Lastly antioxidant supplementation has also been examined to see if it improves cognitive functioning or stabilises cognitive decline in people with dementia and Down’s syndrome.•The reviewers who advised on this vignette were specifically asked what constitutes “usual care” for managing cognitive decline/dementia in adults with Down’s syndrome – opinion was mixed and has been summarised in the “Reviewers’ comments” section below. Cost and implications for NHS spend Adults with Down’s syndrome over the age of 40 years experience an increased level of cognitive decline far greater than people without Down’s syndrome. If adjunctive pharmacotherapy for cognitive decline associated with Down’s syndrome could produce even modest gains in cognitive function then large collective gains to the population of people with Down’s syndrome their families and their communities might be possible. The proposed systematic review should help clarify the current landscape in this area and offer suggestions for priority research.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS