or autism spectrum disorder and dementia

Research in Developmental Disabilities 62 (2017) 50–57

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Research in Developmental Disabilities

Use of antipsychotics, benzodiazepine derivatives, and dementia medication among older people with intellectual disability and/or autism spectrum disorder and dementia Anna Axmon a,∗ , Jimmie Kristensson b , Gerd Ahlström c , Patrik Midlöv d a b c d

Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, SE 221 00 Lund, Sweden Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden Department of Health Sciences, Lund University, SE 221 00 Lund, Sweden Center for Primary Health Care Research, Department of Clinical Sciences in Malmö, Lund University, SE 221 00 Lund, Sweden

a r t i c l e

i n f o

Article history: Received 2 June 2016 Received in revised form 2 January 2017 Accepted 2 January 2017 Number of reviews completed is 2 Keywords: Registry study Anticholinesterases Memantine Drug use Drug prescription Sweden

a b s t r a c t Background: Although people with intellectual disability (ID) and people with dementia have high drug prescription rates, there is a lack of studies investigating drug use among those with concurrent diagnoses of ID and dementia. Aim: To investigate the use of antipsychotics, benzodiazepine derivatives, and drugs recommended for dementia treatment (anticholinesterases [AChEIs] and memantine) among people with ID and dementia. Methods and procedures: Having received support available for people with ID and/or autism spectrum disorder (ASD) was used as a proxy for ID. The ID cohort consisted of 7936 individuals, aged at least 55 years in 2012, and the referent cohort of age- and sex-matched people from the general population (gPop). People with a specialists’ diagnosis of dementia during 2002–2012 were identified (ID, n = 180; gPop, n = 67), and data on prescription of the investigated drugs during the period 2006–2012 were collected. Outcome and results: People with ID/ASD and dementia were more likely than people with ID/ASD but without dementia to be prescribed antipsychotics (50% vs 39% over the study period; odds ratio (OR) 1.85, 95% confidence interval 1.13–30.3) and benzodiazepine derivatives (55% vs 36%; OR 2.42, 1.48–3.98). They were also more likely than people with dementia from the general population to be prescribed antipsychotics (50% vs 25%; OR 3.18, 1.59–6.34), but less likely to be prescribed AChEIs (28% vs 45%; OR 0.32, 0.16–0.64). © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

What this paper adds This paper adds results from a large group of older people with intellectual disability (ID), identified through a register that includes a high proportion of people with ID in Sweden. It also contributes data regarding the prescription of benzodiazepine derivatives, anticholinesterases, and memantine among people with ID and dementia. We have not been able to find such data in any previously published research. Finally, it adds comparisons with a general population sample with regard to the investigated drugs, also something we have failed to find in previously published data.

∗ Corresponding author. E-mail addresses: [email protected] (A. Axmon), [email protected] (J. Kristensson), [email protected] (G. Ahlström), [email protected] (P. Midlöv). http://dx.doi.org/10.1016/j.ridd.2017.01.001 0891-4222/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

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1. Introduction As the life expectancy increases for people with intellectual disability (ID) (Dieckmann, Giovis, & Offergeld, 2015; Janicki, Dalton, Henderson, & Davidson, 1999; Patja, Iivanainen, Vesala, Oksanen, & Ruoppila, 2000) the prevalence of age related diseases such as dementia is expected to increase in this population. However, little is known about drug use among people with concurrent diagnosis of ID and dementia. Such knowledge is important to get a deeper understanding about the treatments provided. Antipsychotics, or neuroleptics, are a range of pharmaceuticals approved primarily for schizophrenia, bipolar disorder, and psychotic disorders. However, off-label prescription to treat challenging behaviors among people with ID is common (Deb, Unwin, & Deb, 2015; Doan, Lennox, Taylor-Gomez, & Ware, 2013; Tsiouris, Kim, Brown, Pettinger, & Cohen, 2013), as is prescription to manage behavioral and psychological symptoms of dementia (BPSD) (Gareri, De Fazio, Manfredi, & De Sarro, 2014). This is in spite of research suggesting that antipsychotics may not be an effective treatment for challenging behaviors (Tyrer et al., 2009), and that the use of these drugs is associated with a range of side effects (Gardette et al., 2012; Huybrechts et al., 2012; Vigen et al., 2011). Although there are antipsychotics that may be effective in the treatment of BPSD (La Malfa, Lassi, Bertelli, & Castellani, 2006), the effectiveness has been questioned (Gauthier et al., 2010). Moreover, the use of these drugs is associated with an increased risk of serious adverse cerebrovascular events (Ballard & Howard, 2006). Even though benzodiazepines are not the usual or recommended treatment, benzodiazepine derivatives are used for epilepsy, sleep disorders, anxiety, and panic disorders. The use of benzodiadepine derivatives have been found to be associated with several adverse effects, e.g. increased risk of falls in older adults (Ham et al., 2014; van Strien, Koek, van Marum, & Emmelot-Vonk, 2013), and should be avoided for treatment of BPSD (Gauthier et al., 2010; Schneider, Dagerman, & Insel, 2006; Sink, Holden, & Yaffe, 2005). Thus, antipsychotics and benzodiazepine derivatives are prescribed to a larger extent than warranted to both people with ID and people with dementia, even though the clinical efficacy for off-label use is questionable and adverse reactions are common and can be severe. The situation is worsened by the fact that both antipsychotics and benzodiazepine derivatives may interact with dementia treatments such as anticholinesterases (AChEIs) and memantine (Pasqualetti, Tognini, Calsolaro, Polini, & Monzani, 2015). Recently, both the American Geriatrics Society (By the American Geriatrics Society Beers Criteria Update Expert, 2015) and the Swedish National Board of Health and Welfare have included antipsychotics as well as benzodiazepines when listing potentially inappropriate drugs among older people (Socialstyrelsen, 2010). The aim of the present study was to investigate drug use, by using purchase of prescribed drugs as a proxy, of antipsychotics and benzodiazepine derivatives in people with ID and dementia in comparison with people with ID but without dementia and people with dementia from the general population. Furthermore, to investigate use of the dementia treatments AChEIs and memantine associated with ID. 2. Materials and methods 2.1. Study population The present study is a register study based on a cohort of people with ID (ID cohort) and an age- and sex-matched referent cohort from the general population (gPop cohort). The cohort comprising people with ID was an administrative one, identified using the so called LSS-register. This register is maintained by the Swedish National Board of Health and Welfare, and contains information on people who have received support and services because of ID, autism, or “a condition resembling autism” (the latter two will be referred to as autism spectrum disorders; ASD). To receive these services, the individual must apply to the municipality, where an investigation is made to determine if the person fulfills the criteria of having ID or ASD, and an assessment of needs is made. All services for all people receiving them are included in the register. However, no information on diagnoses (e.g. ID or ASD) is included. As we were not able to separate those with ID with or without ASD from those with ASD only, we used having received support according to the LSS as a proxy for ID. Through the LSS-register, we identified all 7936 individuals who were 55 years or older in 2012, alive at the end of that year, and had received at least one type of service during the year. A randomly selected referent cohort comprising 7936 people from the general population (gPop), matched one-to-one by birth year and sex, was identified from the Swedish National Population Register. The matching was performed by Statistics Sweden. Diagnoses in the Swedish National Patient register during 2002–2012 were used to identify individuals with dementia (F00-F03, F10.7A, and G30-G31 in International Classification of Disease, 10th revision [ICD-10]; n = 216 in the ID cohort, and n = 81 in the gPop cohort). This implies that all diagnoses were made by physicians in either inpatient care or specialist care according to practice and standards at the time of the diagnosis. Those who contributed with less than one year to the study (36 in the ID cohort and 14 in the gPop cohort), i.e., were diagnosed during 2012, were excluded, leaving 180 people with dementia in the ID cohort and 67 in the gPop cohort. Sex- and age-distributions are presented in Table 1. 2.2. Outcome measures The Swedish Prescribed Drug Register, which is also kept at the Swedish National Board of Health and Welfare, was established in July 2005. This register contains information on all dispensed prescriptions, and is complete for the entire

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Table 1 People with and without dementia among people with intellectual disability (ID) and an age- and sex-matched sample from the general population (gPop). gPop

ID

n Dementia Men Women Time in the study (years)a Age at start of study period (years)a Age at end of study period (years)b No dementia Men Women Age at start of study period (years)c Age at end of study period (years)b a b c

Median (range)

67 33 34

n

Median (range)

180 80 100 3.3 (1–7) 70 (52–89) 76 (55–93)

3.8 (1–7) 60 (47–91) 64 (55–93)

7855 4288 3567

7720 4228 3492 56 (48–90) 63 (55–96)

56 (48–90) 63 (55–96)

People with dementia were not included in the study until their first recorded diagnosis of dementia. December 31st, 2012. January 1st, 2006.

Table 2 Number of people from a general population sample (gPop) and in a group of people with intellectual disability (ID) who were prescribed different antipsychotics and benzodiazepine at least once during 2006–2012. Drugs not included in the table were not prescribed. DDD (oral adm.) gPop with dementia (n = 67) ID with dementia (n = 180) ID without dementia (n = 7720) Antipsychotics Levomepromazine (N05AA02) Haloperidol (N05AD01) Zuclopenthixol (N05AF05) Olanzapine (N05AH03) Risperidone (N05AX08) Benzodiazepine derivatives Diazepam (N05BA01; tablet form only) Oxazepam (N05BA04)

0.3 g 8 mg 30 mg 10 mg 5 mg

1 4 3 2 12

14 11 13 14 43

788 566 511 659 1128

10 mg 50 mg

32

99

2757

Swedish population (Wettermark et al., 2007). Drugs are classified according to the Anatomical Therapeutic Chemical (ATC) classification system (WHO, 2013). For each post, the size of one unit of the drug is given as the Defined Daily Dose (DDD). The DDD is a standardized dose measure defined by the WHO as the assumed average maintenance dose per day for a drug used for its main indication in adults (WHO, 2012). E.g., for antipsychotics, it is based on treatment of psychosis, and for benzodiazepine derivatives on their use as hypnotics. The DDD has been suggested to be an appropriate measure of dose for use in epidemiological studies (Cosentino, Leoni, Banfi, Lecchini, & Frigo, 2000; Merlo, Wessling, & Melander, 1996). The advantage of using a standardized dose measure rather than a measure given in tablets or grams, is the ability to compare use of drugs with different standard doses. E.g., whereas the average daily dose for the antipsychotic Levomepromazine is 300 mg, it is only 5 mg for the antipsychotic Risperidone. Data on the purchase of prescribed antipsychotics (ATC-code N05A) and benzodiazepine derivatives (N05BA and N05CD; i.e., not including drugs prescribed as antiepileptics) were investigated for differences between people with dementia in the ID and gPop cohorts, as well as between people with and without dementia in the ID cohort. Purchases of AChEIs (N06DA) and memantine (N06DX01) were evaluated with respect to differences between people with dementia in the ID and gPop cohorts. Purchase was assessed as having at least one during the study period (2006–2012), as well as number of DDDs. The DDD for oral administration for each drug recorded for the people included in the present study is given in Table 2. 2.3. Ethics Approval was obtained from the Regional Ethical Review Board in Lund (diary no. 2013/15). In addition, the National Board of Health and Welfare as well as Statistics Sweden performed separate secrecy reviews in 2014 before providing access to the data. All analyses were performed using anonymized datasets. 2.4. Statistics To compare the number of people with at least one purchase of each respective drug during the study period, odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression. These analyses were adjusted for year of birth, sex, and time in the study. As data regarding DDD were not normally distributed, group comparisons were made using the Mann-Whitney U test. Since this test does not allow for adjusting of other variables, individual median DDD was divided by the period length. Thus, yearly levels were estimated.

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Fig. 1. Percentage of people with dementia with prescriptions of antipsychotics (grey dotted line), benzodiazepine derivatives (grey solid line), anticholinesterases (black dotted line), and memantine (black solid line) in a group of people with intellectual disability (ID; bottom) and a general population sample (gPop; top). Table 3 People who purchased prescribed drugs at least one time during the study period (2006–2012), and the yearly average of Defined Daily Dose (DDD, median and interquartile range [IQR]) among people with intellectual disability (ID) with (n = 180) and without (n = 7720) dementia, and in a general population sample (gPop) with (n = 67) and without (n = 7855) dementia. gPop n (%) N05A: Antipsychotics 17 (25) With dementia Without dementia 224 (3) N05BA + N05CD: Benzodiazepine derivatives With dementia 32 (48) 973 (12) Without dementia N06DA: Anticholinesterases (AChEIs) 30 (45) With dementia N06DX01: Memantine 16 (24) With dementia a b c

ID a

DDD Median (IQR)

n (%)

DDD Median (IQR)a

12 (5–51) 15 (2–147)

90 (50)b c 3002 (39)

65 (19–192)b c 117 (40–282)

23 (3–51) 5 (1–36)

99 (55)c 2757 (36)

21 (3–66) 16 (3–142)

260 (96–371)

51 (28)b

184 (37–341)

124 (17–241)

30 (17)

105 (34–233)

Median and interquartile range for those with at least one prescription. Statistically significantly different from people with dementia in gPop. Statistically significantly different from people with ID but without dementia.

A two-sided p-value of 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics 23.

3. Results The antipsychotics and benzodiazepine derivatives used in the selection of drugs, as well as the number of people who were prescribed these at least once during the study period, are listed in Table 2. Yearly percentages of prescriptions for the four investigated drugs can be found in Fig. 1. People with dementia in the ID cohort were more likely than people with dementia in the gPop cohort to have purchased antipsychotics at least once during the study period (OR 3.18, 95% CI 1.59–6.34, adjusted for year of birth, sex, and time in the study; Table 3). They were, however, less likely to have purchased AChEIs (0.32, 0.16–0.64). There were no statistically significant differences between the cohorts regarding benzodiazepine derivatives (1.40, 0.75–2.61) or memantine (0.52, 0.24–1.14). People with dementia in the ID cohort who were prescribed antipsychotics had higher median DDD, i.e., higher doses, than their counterparts in the gPop cohort (p = 0.017; Table 3). No statistically significant differences were found for DDD of benzodiazepine derivatives (p = 0.91), AChEIs (p = 0.40), or memantine (p = 0.89). Within the ID cohort, people with dementia were more likely than those without dementia to have purchased antipsychotics (OR 1.85, 95% CI 1.13–30.3, adjusted for year of birth, sex, and time in the study; Table 3). Moreover, those with at least one purchase had higher median DDD (p = 0.001). People with dementia in the ID cohort were also more likely than people

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without dementia in the ID cohort to have purchased benzodiazepine derivatives at least once during the study period (2.42, 1.48–3.98). There were, however, no differences in median DDD among those with at least one purchase (p = 0.77).

4. Discussion In the ID cohort, i.e. among people with ID and/or ASD, dementia was associated with more prescriptions of antipsychotics and benzodiazepine derivatives. People with ID/ASD and dementia were also more likely than those with dementia in the general population to be prescribed antipsychotics, but less likely to be prescribed AChEIs. A major strength of the present study is the use of a national register to collect information on drug prescriptions. The Swedish Prescribed Drug Register contains information, including patient identities, for all dispensed prescriptions in the entire Swedish population (Wettermark et al., 2007). Moreover, drug prescriptions among people without dementia in the general population sample compare well with that for the whole Swedish population with respect to the most commonly prescribed drugs (Socialstyrelsen, 2013), suggesting that the gPop cohort is a representative sample of the general Swedish population with respect to purchase of prescribed drugs. There are, however, also a few weaknesses that need to be considered. First, the purchase of prescribed drugs is used as a proxy for drug use. This is based on the assumption that all purchased drugs are consumed (secondary adherence). Secondary non-adherence has often been found to exceed 50%, with varying levels depending on indication and population (WHO, 2003). Elderly (Mansur, Weiss, Hoffman, Gruenewald, & Beloosesky, 2008; Pasina et al., 2014) and people with ID (Hom et al., 2015; Tan et al., 2015) constitute groups with high rates of non-adherence. Hence, purchases of drugs will tend to overestimate actual drug use, and even more markedly in the present study as it is based on populations with known high rates of non-adherence. Second, people with dementia were identified by primary and secondary diagnoses in the National Patient Register during the years 2002–2012, i.e., we have used dementia diagnoses in inpatient and specialist outpatient care during a specified time period as a proxy for dementia. We do not believe that this has caused us to misclassify people without dementia as having dementia. However, people with dementia who received their diagnoses before 2002, or while in primary care, were misclassified as not having dementia. An indication that this may indeed be the case is that the prevalence of dementia among people from the general population sample (Wittchen et al., 2011) as well as among people with ID (Strydom, Livingston, King, & Hassiotis, 2007) are lower in our study than presented in previous research. A further issue when studying dementia in people with ID is that this diagnosis may go unrecognized as its symptoms are mistakenly interpreted as being connected to the ID itself. Third, the ID cohort is an administrative one. Since the LSS act was passed in 1993, registration for services and support for people with ID is made by application only. However, all people in this study were born before this, during a period when registration for services was more or less automatic for people with an ID diagnosis. Thus, we expect the ID cohort to represent the group of ageing people with ID or ASD in Sweden well. Nevertheless, that diagnoses are not included in the LSS register may pose a problem in that we cannot differentiate those from ID with or without ASD from those with ASD only. It has been estimated that among those receiving LSS support, the group of people with ASD is about half as large as the group of people with ID (Socialstyrelsen, 2011). However, older people, as in the present study, are less likely than younger to have been diagnosed with ASD. Moreover, a large part of people with ASD also have a diagnosis of ID (Bourke, de Klerk, Smith, & Leonard, 2016). Unfortunately, as all analyses were performed on anonymized register data, we found no way to overcome the limitations presented above. However, all identified limitations would result in an underestimation of the true effects. Thus, we feel confident that we have not exaggerated any of the results presented. We present yearly percentages of prescriptions for people with ID/ASD and dementia as descriptive data. These should be interpreted cautiously, as changes from one year to another can be the result of time trends, aging, or more people being diagnosed with dementia. It is, however, noteworthy that the yearly percentage of prescription of antipsychotics is fairly stable at 35%, and that there seems to be a lag in prescription of dementia treatment following the diagnosis of dementia. The yearly antipsychotic prescription rate of 35% is in line with rates found in a Norwegian study including adults with administratively defined ID living in community settings (Holden & Gitlesen, 2004), as well as a study reviewing medical records of people with ID in residential settings in the Netherlands (de Kuijper et al., 2010). It is, however, higher than what was found in group homes in the Netherlands (Stolker, Koedoot, Heerdink, Leufkens, & Nolen, 2002), among adults in a community setting in Australia (Doan et al., 2013), and in a primary health care setting in the U.K. (Molyneux, Emerson, & Caine, 1999) and Catalonia (Rubio-Valera et al., 2012). One likely explanation for the discrepancies is the higher age among those included in the present study compared with those included in the Dutch (74% were 50 years, or younger), Australian (age range 19–71 years), British (74% between 19 and 64 years), and Catalonian (mean age 54 years) studies. Among people with dementia and ID/ASD, the median yearly DDD was 65, which may be translated into e.g. 325 mg Risperidone or 19.5 g Levomepromazine. This was more than five times higher than in what was found in the gPop cohort, suggesting higher doses and/or longer treatment periods among people with ID/ASD and dementia than among people with dementia in the general population. However, the DDD was even higher among people with ID/ASD but without dementia − median yearly DDD was 117, which may be translated into 585 mg Risperidone or 35.1 g Levomepromazine.

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To the best of our knowledge, there are only a few studies regarding prescription and use of AChEIs (Ballard, Mobley, Hardy, Williams, & Corbett, 2016), and no published results regarding benzodiazepine derivatives or memantine among people with ID. In the present study, a high proportion of people with ID/ASD used antipsychotic medication despite a lack of evidence to support this practice and a considerable risk of adverse drug reactions (Scheifes, Stolker, Egberts, Nijman, & Heerdink, 2011; Tsiouris, Kim, Brown, & Cohen, 2011; Tsiouris et al., 2013). The reasons for this potentially improper treatment may be diverse. ID is often accompanied by high rates of difficulties, such as challenging behaviors (Matson & Boisjoli, 2007), and one likely explanation to the high prescription is off-label prescription to treat such behaviors (Deb et al., 2015; Doan et al., 2013; Tsiouris et al., 2013). It may also be that difficulties in interpreting symptoms of psychiatric disorders in people with ID (Holden & Gitlesen, 2009; McBrien, 2003) leads to attempts to treat the symptoms rather than the cause. This may also be caused by difficulties in determining the extent to which presenting behaviors are the result of co-existing psychiatric disorders or the ID itself. Another explanation may simply be that people with ID treated with antipsychotics use these medications for many years (de Kuijper et al., 2013), without being re-evaluated with regard to their need for the medication. Prescriptions of benzodiazepine derivatives were also frequent among people with ID and dementia, although not statistically significantly higher than among people with dementia in the general population. Benzodiazepine derivatives are not first line medications for behavioral problems among people with ID (Expert Consensus Guideline Series, 2000) or in dementia (Gauthier et al., 2010; Schneider et al., 2006; Sink et al., 2005), and they have been found to interact with AChEIs as well as memantine (Pasqualetti et al., 2015). Thus, the use should not be expected to be as common among people with ID and dementia as in the present study. In the general population, benzodiazepine derivatives − although intended for shortterm use − are often prescribed for longer periods to middle-aged and older people (Egan, Moride, Wolfson, & Monette, 2000; Sonnenberg et al., 2012). There is no reason to suspect that circumstances are different among people with ID. The prescription of medication to treat Alzheimer’s dementia is supported by guidelines in most countries (Hort et al., 2010; Segal-Gidan et al., 2011). In the present study, we found a drop in prescriptions of AChEIs shortly after the first diagnosis of dementia among people with ID. It is possible that this was partly due to more use of memantine. Nevertheless, prescription of AChEIs as well as memantine was less frequent among people with ID than in the general population, although statistically significant only for AChEIs. In each individual case, it is not possible to tell whether AChEIs are appropriate or not. However, on a group level this difference may reflect inadequate treatment. This inadequate treatment of dementia in ID compared with the general population in our study may be due to difficulties in interpreting symptoms. Dementia in people with ID may have an atypical presentation. Changes in behavior may precede the typical cognitive symptoms, and the onset of seizures is also common (Strydom et al., 2010). In the treatment of dementia, non-pharmacological treatments are important. However, in this study we had no available data on e.g. psychosocial interventions. People with ID and dementia use more potentially inappropriate medications and less recommended medications compared with the general population with dementia. Clinicians need to be aware of this. Examination and thorough evaluation of treatment is always important in patients with dementia and especially in people with ID and dementia. Adverse effects and response to treatment should be monitored with due consideration to the communication difficulties of the patient. The caregivers of those with limited communication abilities should be provided with clear instructions on how to monitor for positive as well as adverse effects. 5. Conclusions People with ID and dementia were more likely to be prescribed antipsychotics than both people with ID but without dementia, and people with dementia in the general population. Prescription of benzodiazepine derivatives, AChEIs, or memantine was not associated with ID among people with dementia. It was, however, associated with dementia among people with ID. Considering the communication difficulties related to both ID and dementia, the adverse effects of these potentially inappropriate medications need to be monitored. Acknowledgements This study is part of the project OID-Health (Older people with Intellectual Disability and healthy aging) and was funded by Forte (The Swedish Research Council for Health, Working Life and Welfare; diary no 2014-4753). We would also like to acknowledge the cooperation with FUB (The Swedish National Association for People with Intellectual Disability). References Ballard, C., & Howard, R. (2006). Neuroleptic drugs in dementia: Benefits and harm. Nature Reviews Neuroscience, 7(6), 492–500. http://dx.doi.org/10.1038/nrn1926 Ballard, C., Mobley, W., Hardy, J., Williams, G., & Corbett, A. (2016). Dementia in down’s syndrome. 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