A prospective 20-year longitudinal follow-up of ...

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Journal of Intellectual Disability Research

doi: 10.1111/jir.12390

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A prospective 20-year longitudinal follow-up of dementia in persons with Down syndrome M. McCarron,1 P. McCallion,2 E. Reilly,3 P. Dunne,3 R. Carroll1 & N. Mulryan3 1 School of Nursing and Midwifery, Trinity College Dublin, Dublin, Ireland 2 Center for Excellence in Aging & Community Wellness, University at Albany, Albany, NY USA 3 Daughters of Charity Disability Support Service, Dublin, Ireland

Abstract Goal To examine dementia characteristics, age at onset and associated co-morbidities in persons with Down syndrome. Method A total of 77 people with Down syndrome aged 35 years and older were followed up from 1996 to 2015. The diagnosis of dementia was established using the modified ICD 10 Criteria and a combination of objective and informant-based tests. Cognitive tests included the Test for Severe Impairment and the Down Syndrome Mental Status Examination; adaptive behaviour was measured using the Daily Living Skills Questionnaire, and data from the Dementia Questionnaire for People with Intellectual Disabilities have been available since 2005. Results Over the 20-year period, 97.4% (75 of 77) persons developed dementia with a mean age of dementia diagnosis of 55 years (SD = 7.1, median = 56 years). Clinical dementia was associated with cognitive and function decline and seizure activity. Risk for dementia increased from 23% in those aged 50 years to 80% in those aged 65 years and above. There were no differences by level of ID. Conclusion The previously reported high risk levels for dementia among people with Down syndrome Correspondence: Prof Mary McCarron, Faculty of Health Sciences, Trinity College Dublin, Dublin, Ireland. +353 1 896 4148 (e-mail: [email protected]).

were confirmed in this data as was the relationship with late onset epilepsy. The value of the instruments utilised in tracking decline and helping to confirm diagnosis is further highlighted. Keywords dementia, Down syndrome, longitudinal

Introduction In the general population, dementia is generally associated with older age, and the World Health Organisation (WHO 2012) reports age standardised prevalence rates of 5 to 7% in people age 60 years and older. Also, early onset dementia (EOD) is of increasing concern and generally refers to the clinical presentation of dementia before the age of 65 years, with young onset dementia occurring before the age of 45 years (Masellis et al. 2013). The World Alzheimer’s Report offered a prevalence of dementia of between 2 and 10% in people under the age of 65 years (Prince & Jackson 2009). These reports are in stark contrast to the high prevalence rates of dementia reported for people with an intellectual disability (ID) particularly those with Down syndrome (DS) with prevalence rates reported between 15 and 45% in those aged 45 years and older (Prasher & Krishnan 1993). Consensus findings have been that average age of onset among people with DS is between 51 and 56 years and duration averages between 3.5 and 6 years, with individual cases as high

© 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd

Journal of Intellectual Disability Research 2 M. McCarron et al. • 20-year longitudinal follow-up of dementia

as 21 years (Lai & Williams 1989; Prasher & Krishnan 1993). Strydom et al. (2010) in a review of published studies (1997–2008) reported a higher prevalence of dementia in persons with DS, with rates accelerating from 9% in those under 49 years (Coppus et al. 2006), 5.7% to 10.3% in ages 40–49 years (Holland et al. 1998; Tyrrell et al. 2001), 30.4% to 40% in ages 50– 59 years (Holland et al. 1998; Tyrrell et al. 2001; Coppus et al. 2006) and 41.7–50% in those aged 60 to 70 years (Tyrrell et al. 2001). One report is of 100% prevalence rate in adults aged 65 years and over (Visser et al. 1997). In the general population, diagnosing EOD is often fraught with difficulties, and timely diagnosis poses numerous challenges for clinicians, confounded by patient heterogeneity, different clinical features and often confusion with mental health problems. These challenges are further confounded in people with ID and complicated by pre-existing intellectual impairment, difficulty in using standardised tests, communication difficulties, care environment concerns, lack of base line performance data and the consequences of high staff turnover. Achieving accurate diagnosis will only happen if there is a consistent approach to diagnosis, and accurate information available to measure and evaluate change in the context of the individual’s premorbid level of functioning. Consequently, variations in reported prevalence rates are not surprising. The quality of data and associated findings is further compromised by assessments being carried out in crisis, with dementia often already at an advanced stage; published studies with cross-sectional designs and other methodological limitations (Zigman et al. 2002); longitudinal studies of relatively short duration with few data points (see for example, McKensie et al. 1998; Holland et al. 2000; Margallo-Lana et al. 2007) and arguments in the literature that longitudinal follow-up is not useful in people with severe ID (Margallo-Lana et al. 2007). There are also reports of high prevalence of depression (Haveman et al. 2010; Shooshtari et al. 2011) and of epilepsy in people with DS and other intellectual disabilities as they age, and some evidence of association between the prevalence of those additional conditions and of dementia (Patti 2005; Simone et al. 2010; Lott et al. 2012). Also, there are some findings of no difference in age of diagnosis and in duration of dementia by level of ID (Strydom et al. 2009; McCarron et al. 2014).

Prompt and accurate diagnosis of dementia is frequently associated with memory clinics for the general population (Foreman et al. 2004) but has been less so for people with ID with reports that communication barriers, lack of experience in interviewing people with ID, poor understanding of decline in the context of pre-existing impairment and age-based criteria to access services (McCarron & Lawlor 2003). Now, however, there are some memory clinics within ID services (McCreary et al. 1993; Chicoine et al. 1999; Hassiotis et al. 2003; Cahill et al. 2011; McCarron et al. 2016), and the present analysis draws data from such a memory clinic serving primarily women with DS within the Daughters of Charity Disability Support Service in Ireland. This clinic today works with 200 people with DS over the age of 40 years, and the data reported are from an initial cohort of 77 women with DS over age 35 years who have been followed for 20 years from pre morbid levels of functioning examining cognitive and functional decline, co-morbidity and mortality.

Methods This is a prospective longitudinal study of dementia incidence, co-morbidities and mortality in persons with DS reporting on a 20-year follow-up of 77 subjects.

Sample Seventy-seven women with DS over the age of 35 years were enrolled and screened in 1996 and then assessed for symptoms of dementia on an annual basis until death, with assessments completed in a specialist memory clinic. Following recommendations of Aylward et al. (2005), dementia diagnosis was confirmed using ICD-10 criteria.

Assessment protocol Each person received a complete comprehensive assessment at baseline including a carer/family interview; a detailed clinical screen and a medical records review that established level of ID and past and present cardiovascular health, lung disease, diabetes, epilepsy, depression, sensory impairments and gastric disease; and standardised measures of cognitive and physical functioning. The comprehensive clinical screen and cognitive and



physical functioning was then repeated annually during the years each subject was still alive.

Cognitive and physical functioning measures Measures were in two groupings Informant based – Daily Living Skills Questionnaire (DLSQ – NIA 1989). An additional informant-based questionnaire, the Dementia Questionnaire for People with Intellectual Disabilities – DQPID (Evenhuis 1990; 2006), was introduced in 2005 and then repeated each year. Objective based – Down’s syndrome Mental Status Examination (DSMSE – Haxby 1989) and Test for Severe Impairment (TSI – Albert & Cohen 1992) test instruments were administered.

Kaplan–Meier estimator, also known as the product limit estimator, is a non-parametric statistic used to estimate the survival function from lifetime data. It is used to measure the fraction of patients living for a certain amount of time after diagnosis of dementia. Data are right censored. Right censoring occurs when a subject leaves the study before an event occurs, or the study ends before the event has occurred. Life time prevalences (LTPs) were used for dementia, epilepsy and depression, and linear regression was applied to examine the relationship between age and LTP. Life time prevalence is the proportion of a population that at some point in their life (up to the time of assessment) have experienced the condition.

Results Incidence and risk of dementia

The utility of all the instruments in measuring cognitive and functional decline in persons with DS has previously been reported (Tyrrell et al. 1996; Cosgrave et al. 1998; Tyrrell et al. 2001; McCarron et al. 2002; McCarron et al. 2014).

Diagnosis As recommended by Aylward et al. (1995, 1997), the diagnostic workup included a full physical examination, urinalysis, geriatric blood screen and mental health assessment. When other conditions were not established as explaining symptoms observed, new cases of dementia diagnosis were ascertained in a consensus meeting with members of the person’s multi-disciplinary team including the clinical nurse specialist in dementia, caregivers/family, consultant psychiatrist and psychologist using the modified ICD criteria. The study team and assessment protocol were purposefully maintained over the assessment period.

Data analysis Demographics of the sample were examined, and the incidence of dementia over time and patterns in comorbid health conditions were plotted. A 20-year survival curve also plotted the survival proportion as a function of time using the Kaplan–Meier method. The Kaplan–Meier survival curve is defined as the probability of surviving in a given length of time while considering time in many small intervals. The

Over the 20-year follow-up period, 97.4% (75 of 77) of subjects developed dementia. The mean age of dementia diagnosis was 55 years (SD = 7.1, median = 56 years). Of those classified as having moderate ID, 96.7% (59 of 61) had developed dementia by the end of the study period as did 100% (15 of 15) of those classified as having severe ID. Based upon these incidence findings, the risk for developing dementia was mapped by age. As can be seen in Fig. 1, a 23.38% risk was established at age 50 years, 45% at age 55 years and 88% risk by age 65 years. One person died age 52 without a diagnosis of dementia, and the remaining person alive without dementia is aged 61.

Co-morbidities The clinical characteristics and health co-morbidities in persons with dementia are presented in Fig. 2. Several co-morbid diagnoses stand out. A total of 77.9% of the total sample (60 of 77) have a diagnosis of epilepsy. All 60 people with a diagnosis of epilepsy also had a diagnosis of dementia. For the 60 people with epilepsy, the mean age of onset of epilepsy was 55.9 years (SD = 9.53, median = 57 years, min = 20 years, max = 77 years). As may be seen in Fig. 3, diagnosis of dementia and of epilepsy were highly associated. Diagnosis of epilepsy was on average 0.57 (SD = 8.63) years after a diagnosis of dementia. More specifically, for the 75 people with dementia, 20% (15 of 75) did not have a



Figure 1 Cumulative risk of dementia (n = 77). [Colour figure can be viewed at wileyonlinelibrary.com]

diagnosis of epilepsy, 44% (33 of 75) developed dementia before epilepsy, 13.3% (10 of 75) developed both in the same year and 22.5% (17 of 75) developed epilepsy first. Taken together, by three years after dementia diagnosis, 75% (56 of 75) had a diagnosis of epilepsy. In terms of other co-morbidities, by 2015, among those with a dementia diagnosis, 48.0% (36/75) were also diagnosed with depression. Vision impairments were reported in 93.3% (70/75) and hearing impairments in 61.3% (46/75) of subjects with dementia. As may be seen in Fig. 4, the LTP of depression differed somewhat from the prevalence of dementia and epilepsy, with depression appearing to be more prevalent in younger as compared to older ages of dementia and epilepsy onset.

Cognitive and physical functioning measures Graphs were constructed for each instrument’s score using an average of all data available for five years before and five years after the diagnosis of dementia. For the 18 subjects, where in 1996, there was already a diagnosis of dementia, there are no before scores. Similarly, post diagnosis data are limited to those who had developed dementia before 2015. Figure 5 is constructed for the 75 subjects with a diagnosis of dementia by 2015. Unlike the other scales, the DQPID is plotted on a secondary axis and is measured on a reverse scale where higher scores represent an increase in dementia. Decline on the TSI and DSME appeared to occur one year prior to diagnosis, and further decline on

Figure 2 Co-morbidities with dementia (n = 75). [Colour figure can be viewed at wileyonlinelibrary.com]



Figure 3 Life time prevalence (n = 77) of dementia (75 of 77) and of epilepsy (60 of 77). [Colour figure can be viewed at wileyonlinelibrary.com]

these scales was more gradual, post diagnosis. The decline in DLSQ score was over 3–4 years, and decline prior to diagnosis on the DQPID (measured in increased scores), despite the shorter period of administration (only introduced in 2005), appeared more noticeable occurring over a period of five years with post diagnosis decline equally gradual. However, differences were not found to be at statistically significant levels. Rates of decline in scores in the five years pre and post diagnosis for the respective measures may be seen in Table 1 broken out by moderate versus severe and profound levels of ID. Changes in scores were greater for those with moderate ID largely because they began with a higher score (or lower in the case of the DQPID) predementia diagnosis.

Mortality Seventy-four per cent (57 of 77) of the study cohort had died by the end of 2015. Of these, all but one died with a confirmed diagnosis of dementia. Of those who had developed dementia, 74.7% (56 of 75) were dead by 2015, and duration of their dementia was over 6 years (SD = 3.3, median = 7 years); if alive, as of 2015, it was an average of over 8 years (SD = 5.4, median = 6 years). No significant difference in the duration of dementia was observed for those with moderate ID versus those with severe ID (P-value 0.108, t = 1.628). Mean duration for moderate = 6.8 (SD = 3.65). Mean duration severe = 8.6 (SD = 4.8). Nor was there a significant difference (t = .725, df = 17, P-value = 0.478) in the mean age of diagnosis

Figure 4 Life time prevalence (n = 77) of dementia (75 of 77), of epilepsy (60 of 77) and of depression (32 of 77). [Colour figure can be viewed at wileyonlinelibrary.com]



Figure 5 Instrument scores before and after dementia diagnosis, TSI (n = 75), DSMSE (n = 75), ADL (n = 75) and DMR (n = 45). [Colour figure can be viewed at wileyonlinelibrary.com]

of dementia for those with moderate ID (mean = 55.98, SD = 6.1, N = 59) versus those with severe ID (mean = 54.13, SD = 9.4, N = 15). Figure 6 presents the survival curve for the 75 subjects with dementia using the Kaplan–Meier method with the 95% confidence interval. The survival curve plots the survival proportion as a function of time. Time zero represents the year a subject was diagnosed with dementia. The median survival time was 7 years, the time at which half the subjects have died and half are still alive. Logistic regression examined age of onset of dementia, epilepsy and level of ID as predictors of death among the sample see Table 2. Here, epilepsy was found to be the only significant predictor of

mortality (P-value ≤ 0.001). A subject with epilepsy was 11.3 (2.0, 41.9) times more likely to have died than a subject without diagnosed epilepsy when adjusted for age of onset of dementia and level of ID.

Discussion The risk for dementia confirmed by 20 years of data was 23% risk at age 50 years, 45% at age 55 years and 88% risk at age 65 years. This finding is in line with many previous studies (Prasher, 1995; Holland et al. 2000; Zigman et al. 2002) but lower than reports by Visser et al. (1997) and higher than in at least one longitudinal study (Margallo-Lana et al., 2007), which reported a 50% risk at age 60 and

Table 1 Mean annual decrease (increase for DQPID) in TSI, DLSQ, DLSQ and DQPID scores in five years before and five years after dementia diagnosis for persons with moderate and severe ID

Moderate

Severe

TSI AVERAGE 5 years before 4 years before 3 years before 2 years before 1 year before Diagnosis 1 year after 2 years after 3 years after 4 years after 5 years after

15.7 17.3 17.7 16.6 15.8 15.5 11.9 8.6 6.4 2.6 3.6

3 2.6 2.8 1.5 1.6 1.8 0.4 0.7 0.5 1.6 0.5

Moderate

Severe

DSMSE AVERAGE 7 7.9 8.4 8.2 8.5 7.3 6.1 3.6 3 1.6 1.5

0 0 0 0 0 0 0 0 0 0 0

Moderate

Severe

DQPID AVERAGE 21.7 26.1 27 27.1 33.3 45.6 51 58.7 67.4 72.9 74.8

66 60 66 67 65.5 60.5 58.3 71.6 76.4 79.9 82

Moderate

Severe

ADL AVERAGE 14.4 16 15.3 15.3 15.9 12.5 9.4 7.2 5.8 4.4 4

4.2 5.3 6.3 5.6 6.5 5.3 3.6 3.7 1.9 1.5 1.9



Figure 6 Survival curve for subjects with dementia (n = 77). [Colour figure can be viewed at wileyonlinelibrary.com]

above. The average age of diagnosis of dementia at 55 years (SD = 7.1, median = 56 years) was in the higher range of previously reported estimates (51– 56 years), and mean duration of life for those that have died post diagnosis of 5.6 years (SD = 3.26, median = 7 years) years was similarly at the high end of estimates (3.5–6.0 years) (Lai & Williams 1989; Prasher & Krishnan, 1993). The survival curve reported here noted a median survival of seven years; that dementia is just as likely to be for an extended period found here differs from some prior reports of precipitous decline (Lai & Williams 1989) and has major implications from a care and resource perspective in terms of environmental capability,

staff competency and nursing-related care needs. Here, for those with a pre-existing severe or profound level of ID, duration post-diagnosis was for an average 8.6 years despite no significant difference in age of onset as compared to persons with DS at a moderate level of ID confirming previous findings of no difference (Strydom et al. 2009; McCarron et al. 2014). Interestingly, as was previously reported (McCarron et al. 2014), several of the instruments, particularly the DQPID, continue to indicate that there is a gradual decrease in functioning prior to the onset of dementia, suggestive perhaps of pre-clinical dementia in those with DS. As well as supporting the

Table 2 Predictors of mortality

95% confidence interval for OR Dead y/n† Age of onset dementia ID (moderate) Epilepsy (yes)

Sig. .983 .541