Down syndrome in adults: a 27-year follow-up of adaptive skills

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1 Clin Genet 2016: 90: Printed in Singapore. All rights reserved Short Report 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: /cge Down syndrome in adults: a 27-year follow-up of adaptive skills Arvio M., Luostarinen L. Down syndrome in adults: a 27-year follow-up of adaptive skills. Clin Genet 2016: 90: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2016 In 1988, we assessed the adaptive skills of 45 adults with Down syndrome (DS) (21 women and 24 men, age 20 58) with the Portage scale. Since then, we have followed them and also screened for signs of clinical dementia with the Present Psychiatric State Learning Disabilities assessment. The mean adaptive age (AA) of the study group decreased with increasing age; the age of 35 being the turning point in the clinical course of DS. The mean AA was 4.4 years between ages 20 and 34, 3.4 years between ages 35 and 49, and 2.4 years between ages 50 and 66. Inter-individual variation was, however, large. Between ages 20 and 25, the AA of the study subjects ranged from 2.3 to 6 years; and after the age of 50, from 0.3 to 4.8 years. By the end of the study, all subjects showed signs of clinical dementia. These appeared most frequently as reduced self-care skills, loss of energy, forgetfulness, and impaired understanding. We found no connection between apolipoprotein E genotype and the clinical course of DS. We recommend follow-up of adaptive skills and screening for dementia signs in adults with DS. Conflict of interest The authors declare that there is no conflict of interest. M. Arvio a,b and L. Luostarinen a a Päijät-Häme Joint Municipal Authority, Lahti, Finland and b Turku University Hospital, Turku, Finland Key words: aging dementia Down syndrome follow-up Corresponding author: Maria Arvio, Arvi Kariston katu 4b10, Hämeenlinna, Finland. Tel.: ; fax: ; maria.arvio@phsotey.fi Received 16 December 2015, revised and accepted for publication 7 April 2016 Down syndrome (DS) is the most common genetic cause for intellectual disability (ID). Those with DS represent 10 15% of the ID population (1), with abnormally slow development in childhood and premature aging in adulthood as their main characteristics (2, 3). The developmental age of adolescents and young adults usually corresponds that of 4 6 year old healthy children (2). Alzheimer s disease (AD) neuropathology is observable in virtually all individuals by the age of 40 years (4 6). Apolipoprotein (APO) E4 genotype is considered as a risk factor for early dementia and death (7, 8). Adaptive behavior reflects an individual s competence in daily skills to meet the demands of life. In diagnosing ID, professionals assess adaptive skills (communication, daily living skills, socialization and motor skills), in addition to intelligence quotient. Individuals with ID need the aid of others throughout their lives. Those with relatively good adaptive skills can live quite independently in a group home and also work, for instance, as assistants in a warehouse; while those with poor skills need constant assistance around the clock. We aimed to determine the clinical course of adaptive skills and identify signs of clinical dementia in individuals with DS in a longitudinal study for 27 years. Patients and methods Finland was divided into 16 state-supported regional full-service districts, providing residential care, education, rehabilitation, medical follow-up, shelter work, and day activity for individuals with ID, back in the late 1960s. In 1988, the client register of the South Häme district, with a total population of 340,000, included names of 229 persons with DS; of these 184 were older than 19. The study subjects were invited according to the following criteria: DS without evidence of chromosomal mosaicism, age 19+, and a follow-up appointment with the first author during summer A total of 45 adults, 21 women and 24 men, meeting the inclusion criteria were willing to participate. 456

2 Down syndrome in adults Table 1. Clinical data of the study group at the baseline and at the end of the study Women; n (%) Men; n (%) Women; n (%) Men; n (%) 21 (47) 24 (53) 8 (47) 9 (53) Age in years (38) 9 (37) (29) 4 (17) (24) 7 (29) 3 (37.5) 2 (22) (9) 4 (17) 3 (37.5) 6 (67) (25) 1 (11) State of health Alzheimer disease, confirmed? a?? 5 (63) 4 (44) Visual impairment 2 (10) 0 3 (38) 0 Congenital heart defect 2 (10) 3 (13) 0 0 Diabetes type 1 1 (5) 2 (8) 1 (13) 1 (11) Epilepsy 4 (20) 4 (17) 1 (13) 3 (33) Hypothyroidism 6 (29) 6 (25) 3 (38) 4 (44) Psychiatric disorder 2 (10) 3 (13) 2 (25) 2 (22) Hypercholesterolemia b?? 0 2 (22) Gout (22) Hirschprung disease, stoma 0 2 (8) 0 2 (22) Urinary infection (25) 0 No health problem 4 (20) 3 (13) 0 0 Accommodation With relatives 11 (52) 11 (46) 1 (12) 0 Nursing home 10 (48) 13 (54) 7 (88) 9 (100) Severity of ID at adolescence Mild 1 (5) 0 1 (13) 0 Moderate 8 (38) 15 (63) 3 (37.5) 7 (78) Severe 11 (43) 8 (29) 3 (37.5) 2 (22) Profound 1 (14) 1 (8) 1 (13) 0 ID, intellectual disability. a Alzheimer disease diagnostics were considered only in late 1990s. The diagnosis was confirmed with brain magnetic resonance image. b Cholesterol levels were not systemically determined in All assessments were carried by the same two special nurses during home visits and by the following evaluation methods: In 1988: Health status determination, verification of the level of ID at adolescence according to their records. In 1988, 1992, 1995, 1999, 2003, and 2015: An adaptive age (AA) assessment with the Portage scale (9). This includes 527 questions which assess an individual s social, verbal, self-help, cognitive, and motor skills. Portage is primarily intended as an early intervention tool, but in Finland, this method has served in the follow-up of individuals of all ages with a moderate, severe, or profound ID (10). In 2001: APO E genotype testing to 31 study subjects. In 2001 and 2012: Screening for signs of clinical dementia with Present Psychiatric State Learning Disabilities assessment (11 13). In 2015: Health status determination of surviving study subjects, and collection of the ages and causes of death of deceased study subjects. Relationship between AA and chronological age was estimated using random-effects [generalized least squares (GLS)] regression with quadratic term, subject identifier as a random effect; this method accounts for the correlated structure of dependent variables arising from repeated measures over time, controlling for each individual. Bootstrap estimation was used to derive a 95% confidence interval of curvilinear correlation. The Pirkanmaa Hospital District s ethics committee reviewed and supported our study. Written informed consent came from each of the study subjects or from their caretaker or both. Results Clinical data of the 45 study subjects is shown in Table 1. At baseline, 84%, and, at the end of the study, every subject had at least one longstanding health problem or impairment. During the follow-up period, the size of the study group decreased. The caretakers of three subjects refused participation in the final evaluation in Twenty-five (12 women and 13 men) died, median age at death being 57 (range: 36 65). 457

3 Arvio and Luostarinen 8 Men Women Curvilinear correlation = 0.50 (95% CI: 0.26 to 0.67) Curvilinear correlation = 0.59 (95% CI: 0.44 to 0.71) 7 6 Adaptive age in years Chronological age in years Chronological age in years Fig. 1. Adaptive ages according to the Portage scale of 45 adults with Down syndrome by chronological age, 1 6 assessments/individual, in total 199 assessments. Non-linear quadratic models with 95% confidence intervals. Difference between gender p = Figure 1 shows AAs of 45 study subjects (1 6 AAs/subject, total of 199 AAs) in terms of chronological age. Inter-individual variation was large. Between ages 20 and 25, the AA ranged from 2.3 to 6 years; and after the age of 50 from 0.3 to 4.8 years. The mean AA of the study group decreased with increasing age; age 35 being the mean turning point (Fig. 1). The mean AA was 4.4 years between ages 20 and 34, 3.4 years between ages 35 and 49, and 2.4 years between ages 50 and 66. In APO genotype testing, 19 (61%) subjects had E3/E3, 9 (29%) E4/E3, 2 (6%) E4/E4, and 1 (3%) E3/E2. Figure S1, Supporting information shows AAs of 31 study subjects (2 6 AAs/subject, total of 159 AAs) representing different APO genotypes. There was no connection between the clinical course of adaptive skills and APO genotype. Of the 25 deceased study subjects, 12 were alive in 2001 and gave a sample for genotype testing. The median age at death of those 8 with E3/E3 was 58 (range: 45 65). The ages at death of the 4 with E4/E3 were 36, 58, 58, and 62. The cause of death was paralytic ileus associated with diagraphic hernia in a 36 year old man (APO E4/E3, normal brain MRI at the age of 33; minor changes suggesting AD in neuropathological post-mortem); congenital heart defect associated with diabetes mellitus type 1 in a 39 year old man (no APO genotype testing); cortical multi-infarction related to Moyamoya in a 45 year old woman (APO E3/E3); and laryngeal cancer in a 57 year old man (APO E3/E3). For 21 study subjects, the cause of death was AD. Of these, 12 had undergone brain imaging, and 1 neuropathological examination showing AD-characteristic findings, and 4 a routine autopsy. In 19 study subjects (9 women and 10 men) for whom we obtained follow-up data during , Table 2 shows signs of clinical dementia. These signs appeared most frequently as reduced self-care skills, loss of energy, forgetfulness, and impaired understanding. The adolescent level of ID and the number of dementia signs showed no correlation. Discussion The health problems common in elderly people are becoming more frequent in daily medical ID practice as the number of senior-aged citizens with ID continues growing (14). A fact long known is that DS is a risk factor for AD and for Moyamoya-related vascular dementia (4, 15, 16). In two recent studies, the median age of dementia development was 55.5 in those with DS (17, 18). This age appears high, because as neuroradiological and neuropathological studies report AD-characteristic findings already evident at the age of 40 (4 6). In our longitudinal study, age 35 was the turning point in the clinical course of DS, in accordance with radiological and laboratory findings. Further, in our study the signs of clinical dementia were frequent already at the mean age of 41 but continued increasing with age (Table 2). Dementia signs in our study were quite the same: reduced self-care skills, loss of energy, forgetfulness, and impaired understanding, as in a recent study, although those Italian colleagues used other expressions like deficit in verbal comprehension, along with social isolation, loss of interest, and greater fatigue in daily tasks (18). The British study reported frontal lobe -related dementia symptoms like general slowness, language problems, loss of interest in activities, social withdrawal in adults 458

4 Down syndrome in adults Table 2. Signs indicating dementia in 19 study subjects according to Present Psychiatric State Learning Disabilities checklist tested in 2001 and Age, range, mean 34 54, , 52 Sign n (%) n (%) Autonomic anxiety 4 (21) 7 (37) Change in appetite 4 (21) 4 (21) Changed sleep pattern 3 (16) 6 (32) Coarsening of personality 2 (11) 9 (47) Confusion 2 (11) 5 (26) Delusions 2 (11) 5 (26) Diurnal mood variation 6 (32) 8 (42) Forgetfulness 4 (21) 14 (7) Forgetting people s names 1 (5) 3 (16) Geographical disorientation 2 (11) 7 (37) Impaired understanding 5 (26) 15 (79) Irritability 4 (21) 10 (53) Loss of concentration 4 (21) 11 (58) Loss of energy 6 (32) 15 (79) Loss of literacy skills 1 (5) 5 (26) Misery 6 (32) 8 (42) Onset of or increase in other 3 (16) 9 (47) maladaptive behavior Onset of or increase in physical 4 (21) 7 (37) aggression Onset of or increase in verbal 1 (5) 3 (16) aggression Onset of or increased fearfulness 4 (21) 8 (42) Reduced quantity of speech 4 (21) 13 (68) Reduced self-care skills 4 (21) 17 (89) Social withdrawal/reduced social 1 (5) 7 (37) interaction Tearfulness 4 (21) 7 (37) Temporal disorientation 4 (21) 8 (42) Weight change 3 (16) 8 (42) Worry 5 (26) 9 (47) with DS. These symptoms were common also in our study subjects (19). Some studies suggest APO E4 genotype as an additional AD risk factor in those with DS (4, 7, 8). In our small sample, the clinical course of adaptive skills (Fig. S1) and also ages at death of those with E4 genotype were the same as in subjects with other genotypes. The strength of our study is the long follow-up time of adult patients and thorough analysis of adaptive skills assessed by the same professionals. The weaknesses of our study were the small sample and the fact that the study members were not of the same age at the study s initiation. However, as the researches also become older, prospective follow-up studies of adult patients ones lasting for several decades, may be impossible. Dementia diagnostics in the ID population is challenging (20). This population consists of individuals of great variety; firstly, because of their multiple etiologies (genetic, acquired, or multifactorial), secondly because of large heterogeneity in the severity of ID, and thirdly because of neuropsychiatric comorbidities like autism. On the other hand, in the diagnostic workup the fact that those with ID have undergone several psychological evaluations, and most of them, also brain imaging in childhood and adolescence is helpful. Dementia and ID are both signs reflecting disturbed cortical function. ID is diagnosed in childhood and dementia usually in adulthood. In those with ID, the signs of clinical dementia may quite rapidly have a huge impact upon a person s life, resulting in personal discomfort and permanent placement in a nursing home. We therefore suggest regular follow-up of adaptive skills and paying special attention to a healthy lifestyle and to nutrition in adults with DS. 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