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      Predictors of Age of Diagnosis and Survival of Alzheimer’s Disease in Down Syndrome

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          Abstract

          Background:

          People with Down syndrome (DS) are an ultra-high risk population for Alzheimer’s disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade.

          Objective:

          This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these.

          Methods:

          Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated.

          Results:

          The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment.

          Conclusion:

          This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.

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          Most cited references26

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          Survival in dementia and predictors of mortality: a review.

          Dementia is an important cause of mortality and, with the ageing population and increasing prevalence of dementia, reliable data on prognosis and survival will be of interest to patients and caregivers as well as providers and commissioners of health and social care. A review of the literature was undertaken to determine the rates of survival in dementia and Alzheimer's disease (AD) and to identify factors that are or are not predictive of mortality in dementia and AD. Relevant articles on mortality in dementia were identified following a search of several electronic databases from 1990 to September 2012. Inclusion criteria were reports on prospective community or clinic based cohorts published in English since 1990, to reflect more recent recognition of possible predictors. Median survival time from age of onset of dementia ranges from 3.3 to 11.7 years, with most studies in the 7 to 10-year period. Median survival time from age of disease diagnosis ranges from 3.2 to 6.6 years for dementia or AD cohorts as a whole. Age was consistently reported as a predictor of mortality, with male gender a less consistent predictor. Increased disease severity and functional impairment were often associated with mortality. Substantial heterogeneity in the design of included studies limits the ability to prognosticate for individual patients. However, it is clear that dementia and AD are associated with significant mortality. Reasons for the increased mortality are not established. Copyright © 2013 John Wiley & Sons, Ltd.
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            Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up.

            To provide estimates of survival after onset of dementia by age, sex, self reported health, disability, and severity of cognitive impairment. Analysis of participants from prospective population based cohort study in 1991-2003, with follow-up of dementia status in all individuals after two and six years (in one centre) and 10 years and in subsamples additionally at six and eight years and mortality until 2005. Multicentre population based study in England and Wales: two rural and three urban centres. 438 participants who developed dementia from a population based study of 13 004 individuals aged 65 years and over drawn from primary care population registers. Sociodemographic factors, cognitive function, specific health conditions, and self reported health collected at each interview. Cox's proportional hazards regression models were used to identify predictors of mortality from the selected variables in people who received diagnosis of dementia according the study's criteria. By December 2005, 356 of the 438 (81%) participants who developed dementia during the study had died. Estimated median survival time from onset of dementia to death was 4.1 years (interquartile range 2.5-7.6) for men and 4.6 years (2.9-7.0) for women. There was a difference of nearly seven years in survival between the younger old and the oldest people with dementia: 10.7 (25th centile 5.6) for ages 65-69; 5.4 (interquartile range 3.4-8.3) for ages 70-79; 4.3 (2.8-7.0) for ages 80-89, and 3.8 (2.3-5.2) years for ages > or =90. Significant factors that predicted mortality in the presence of dementia during the follow-up included sex, age of onset, and disability. These analyses give a population based estimated median survival for incident dementia of 4.5 years. Such estimates can be used for prognosis and planning for patients, carers, service providers, and policy makers.
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              The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome.

              The form and distribution of senile plaques (SP) and neurofibrillary tangles (NFT) has been examined in the brains of 13 patients with Down's syndrome (DS), aged less than or equal to 50 years, using immunocytochemical and silver staining procedures. SP become present within the brain before NFT and these appear firstly as fine, even, diffuse areas of anti-amyloid (A4) protein immunoreactivity in the absence of any discernable neuritic change. Later the amount of anti-A4 protein in SP increases and SP show a marked surrounding neuritic response which is detectable using either silver or anti-paired helical filament (PHF) staining methods. At this stage NFT also become detectable within the perikaryon of nerve cells in both the cortex and the subcortex, with the large stellate neurones of layer II of the entorhinal cortex showing an early involvement. By the age of 50 years, most patients are well on the way towards achieving (and some have already achieved) that pattern of SP and NFT morphology and distribution that is typically seen in patients over 50 years of age with DS and in other patients in the general population with Alzheimer's disease.
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                Author and article information

                Contributors
                Role: Handling Associate Editor
                Journal
                J Alzheimers Dis
                J. Alzheimers Dis
                JAD
                Journal of Alzheimer's Disease
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                1387-2877
                1875-8908
                6 December 2017
                19 December 2017
                2018
                : 61
                : 2
                : 717-728
                Affiliations
                [a ]Division of Psychiatry, University College London , London, UK
                [b ] Sheba Medical Center , Tel Hashomer, Israel
                [c ]Cornwall Partnership Foundation NHS Trust, UK
                [d ]Westminster Learning Disability Partnership, Central and North West London NHS Foundation Trust, London, UK
                [e ]Livewell SouthWest (CIC), Plymouth, UK (data from South London and Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK)
                [f ] Plymouth University Peninsula School of Medicine and Dentistry , Plymouth, UK
                [g ]Barnet Enfield and Haringey Mental Health NHS Trust, UK
                [h ]Surrey and Borders Partnership NHS Foundation Trust, Epsom, UK
                [i ]Enfield Integrated Learning Disabilities Service, Enfield, UK
                [j ]Camden and Islington NHS Foundation Trust, London, UK
                [k ]Plymouth Teaching Primary Care Trust (now known as Livewell Southwest CIC), UK
                [l ] Institute of Psychiatry , Psychology and Neuroscience, King’s College London, London, UK
                [m ] Hertfordshire Partnership University NHS Foundation Trust , UK
                [n ]Sutton MHLD Team, SW London and St George’s Mental Health NHS Trust, Surrey, UK
                [o ] St George’s University of London , UK
                [p ]Royal Borough of Kensington and Chelsea Learning Disabilities Service, London, UK
                [q ] Institute of Neurology , Queen Square, Education Unit, London, UK
                [r ] Department of Community Mental Health , RAF Marham, Norfolk, UK (data from East London NHS Foundation Trust, UK)
                [s ] Essex Partnership University NHS Foundation Trust , UK
                [t ]The LonDownS Consortium
                Author notes
                [1]

                These authors contributed equally to this work.

                [* ]Correspondence to: Dr. Andre Strydom, Division of Psychiatry, University College London, London, UK. Tel.: +44 02076799308; E-mail: a.strydom@ 123456ucl.ac.uk .
                Article
                JAD170624
                10.3233/JAD-170624
                6004911
                29226868
                c043a31f-6133-4e9c-9ca6-85fb8e719c4a
                © 2018 – IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY 4.0) License.

                History
                : 26 September 2017
                Categories
                Research Article

                alzheimer’s disease,dementia,down syndrome,mental retardation,survival

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