Received: 6 April 2020 Revised: 1 May 2020 Accepted: 4 May 2020 Published online: 25 June 2020 DOI: 10.1002/dad2.12047 DIAGNOSTIC ASSESSMENT & PROGNOSIS Diagnosis of prodromal and Alzheimer’s disease dementia in adults with Down syndrome using neuropsychological tests Bessy Benejam1 Laura Videla1,2,3 Eduard Vilaplana2,3 Isabel Barroeta2,3 Maria Carmona-Iragui1,2,3 Miren Altuna2,3 Silvia Valldeneu2,3 Susana Fernandez1 Sandra Giménez5 Florencia Iulita2,3 Diana Garzón2 Alexandre Bejanin2,3 David Bartrés-Faz4 Sebastià Videla3 Daniel Alcolea2,3 Rafael Blesa2,3 Alberto Lleó2,3 Juan Fortea1,2,3 1 Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain 2 Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 3 Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain 4 Department of Medicine, Faculty of Medicine and Health Sciences, Institute of neurosciences, University of Barcelona, Barcelona, Spain 5 Multidisciplinary Sleep Unit, Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Correspondence Dr. Juan Fortea, Memory Unit, Department Abstract of Neurology, Hospital of Sant Pau, 08025 Introduction: We aimed to define prodromal Alzheimer’s disease (AD) and AD demen- Barcelona, Spain. Email: jfortea@santpau.cat tia using normative neuropsychological data in a large population-based cohort of adults with Down syndrome (DS). Funding information Instituto de Salud Carlos III, Grant/Award Methods: Cross-sectional study. DS participants were classified into asymptomatic, Numbers: PI14/01126, PI17/01019; National prodromal AD and AD dementia, based on neurologist’s judgment blinded to neuropsy- Institutes of Health, Grant/Award Numbers: 1R01AG056850–01A1, R21AG056974, chological data (Cambridge Cognitive Examination for Older Adults with Down’s syn- R01AG061566; Departament de Salut de la drome [CAMCOG-DS] and modified Cued Recall Test [mCRT]). We compared the cut- Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut, Grant/Award Num- offs derived from the normative data in young adults with DS to those from receiver- ber: SLT002/16/00408; Fundació La Marató de operating characteristic curve (ROC) analysis. TV3; Generalitat de Catalunya Results: Diagnostic performance of the CAMCOG-DS and modified Cued Recall Test Bessy Benejam and Laura Videla have equally (mCRT) in subjects with mild and moderate levels of intellectual disability (ID) was high, contributed to this study. both for diagnosing prodromal AD and AD dementia (area under the curve [AUC] 0.73– 0.83 and 0.90–1, respectively). The cutoffs derived from the normative data were simi- lar to those derived from the ROC analyses. Discussion: Diagnosing prodromal AD and AD dementia in DS with mild and moderate ID using population norms for neuropsychological tests is possible with high diagnostic accuracy. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. ○ c 2020 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer’s Association Alzheimer’s Dement. 2020;12:e12047. wileyonlinelibrary.com/journal/dad 1 of 10 https://doi.org/10.1002/dad2.12047 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2 of 10 BENEJAM ET AL . KEYWORDS Down syndrome, Alzheimer’s disease, dementia, cognitive testing, assessment, CAMCOG-DS, Cued Recall Test, normative data 1 INTRODUCTION level of ID for the CAMCOG-DS and the mCRT, a cognitive battery and an episodic memory test widely used in DS, and to assess their perfor- Due to advances in medical care, life expectancy has increased mance to diagnose prodromal AD and AD dementia in adults with DS. significantly in people with Down syndrome (DS), now exceeding 60 years of age.1,2 As a consequence, individuals with DS are now expe- riencing a high incidence of age-associated health problems,3 espe- 2 METHODS cially Alzheimer’s disease (AD) dementia. Pathological studies show that by the age of 40 years, virtually all individuals with DS have AD 2.1 Participants neuropathology,4 and longitudinal studies show that the cumulative incidence of dementia in adults with DS is in excess of 90% by age 65.1,5 Single-center cross-sectional study. Adults with DS were recruited Symptomatic AD increases exponentially with age, with a mean age at from February 1, 2013 to December 31, 2018 at the Alzheimer- dementia onset of between 53.7 and 55.8 years,6,7 and approximately Down Unit from the Catalan Down Syndrome Foundation and Hospi- 50% of cases of dementia are being diagnosed in the sixth decade of tal de la Santa Creu i Sant Pau, in Barcelona, Spain. The Alzheimer- life.6,7 This association between DS and AD is explained mainly by the Down Unit leads a population-based health plan for adults with DS, presence of an extra copy of the amyloid precursor protein (APP) gene, which includes yearly neurological and neuropsychological assess- located on chromosome 21.8 ments. All adults (≥18 years) with DS were eligible, irrespective of sex The diagnosis of prodromal AD and AD dementia in DS is a major or level of ID. Patients showing any psychiatric or medical disorder that challenge. Early symptoms of AD can be mistaken as part of the lifelong could affect cognition and/or functionality were excluded, as well as intellectual disability (ID), or they may be overlooked or misdiagnosed. those with incomplete neuropsychological examinations (flow chart in In the general population, the diagnosis of mild cognitive impairment Figure 1). requires a change in cognition reported by the patient and/or caregiver, The study was approved by the Sant Pau Ethics Committee follow- and is based on cognitive performance on neuropsychological tests rel- ing the standards for medical research in humans recommended by the ative to population norms, and dementia is diagnosed when cognitive Declaration of Helsinki and reported to the Minister of Justice accord- decline affects the activities of daily living. In people with DS, the vari- ing to the Spanish law for research in people with intellectual disabil- able degree of ID problematizes these definitions. Furthermore, most ities. All participants or their legally authorized representative gave test batteries commonly used in the general population are of limited written informed consent before enrollment. use in DS, as many individuals score at floor and noncompletion rates are high.9,10 Adapted tests have been developed to detect cognitive decline in 2.2 Neurological assessment DS, such as the Down Syndrome Mental Status Examination (DSMSE), the Test for Severe Impairment (TSI), the Cambridge Cognitive Exam- The study procedures included a complete neurological examination ination for Older Adults with Down’s Syndrome (CAMCOG-DS), and with the participant and his/her main caregiver. The neurologist per- the Arizona Cognitive Test Battery (ACTB) or the modified Cued Recall formed a physical exam, a structured medical history based on the DS- Test (mCRT).3,9,11-19 However, unlike in the general population, in Connect questionnaire,21 a neurological exam, and a semi-structured adults with DS we are lacking normative data due to the large sample health questionnaire (Cambridge Examination for Mental Disorders of sizes needed to account for the different levels of ID and its associated Older People with Down’s Syndrome and others with intellectual dis- variability in cognitive abilities. Furthermore, although the diagnostic abilities [CAMDEX-DS]) with the caregiver. The CAMDEX-DS is a diag- performance of several adapted tests has been assessed, most of the nostic tool based upon CAMDEX-R and modified for the detection of studies have used small sample sizes and did not take into account the dementia in people with ID.20 It is also adapted and validated for the level of ID. Therefore, the diagnosis of prodromal AD or AD dementia Spanish population with ID.22 using neuropsychological tests in this population at the cross-sectional level is difficult and cannot be made reliably on the basis of neuropsy- chological tests using population norms.20 2.3 Neuropsychological assessment Taking advantage of the Down Alzheimer Barcelona Neuroimaging initiative (DABNI), a large population-based cohort of adults with DS, The neuropsychological test battery for detecting dementia included the purpose of our study was to define population norms stratified by the Cambridge Cognitive Examination for Older Adults with Down’s 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BENEJAM ET AL . 3 of 10 Syndrome (CAMCOG-DS) Spanish version22 and the mCRT,18 both directly administered to the patient. It also included the Demen- RESEARCH IN CONTEXT tia Questionnaire for People with Learning Disabilities (DLD), an 1. Systematic review: Literature was reviewed through informant-based questionnaire to assess cognitive and functional PubMed and meeting abstracts. Due to the variability of decline due to dementia.23 intellectual functioning in people with Down syndrome The CAMCOG-DS has a maximum score of 109 points and com- (DS), there are no accepted population-based neuropsy- prises subscales for the following cognitive domains: orientation, lan- chological normative data and very few studies investi- guage, memory, attention, praxis, abstract thinking, and perception. gating the diagnostic performance of cognitive tests for The mCRT is an adapted test used to assess episodic memory in peo- diagnosing prodromal Alzheimer’s disease (AD) and AD ple with ID. Participants are asked to memorize 12 stimuli presented on dementia in this population. three, 4-item cards. The test consists of three trials of free and cued 2. Interpretation: In a large population-based cohort of recall performed immediately after the learning phase to compute a adults with DS with mild and moderate levels of intellec- free recall score and a total score (free recall + cued recall). For the tual disability (ID), neuropsychological normative data for present study we used the total score (maximum score of 36), as it was Cambridge Cognitive Examination for Older Adults with shown to be more sensitive to detect memory decline in DS.19 Down’s Syndrome (CAMCOG-DS) and modified Cued Recall Test (mCRT) were provided. We show that a diag- nosis of prodromal AD and AD dementia can be done with 2.4 Level of ID high diagnostic accuracy. 3. Future directions: Our results support the use of the The level of ID was categorized according to the Diagnostic and Statisti- CAMCOG-DS and mCRT as screening tools for the diag- cal Manual of Mental Disorders, Fifth Edition (DSM-V) as mild, moderate, nosis of AD in people with DS with mild and moderate ID. severe, or profound, and was based on caregivers’ reports of the indi- Our cutoffs could be used for screening purposes in both viduals’ best-ever level of functioning. The Kauffman Brief Intelligence clinical practice and research settings. Test (K-BIT) was also included to assess pre-morbid intelligence level. 2.5 Diagnostic categories define cutoffs for the neuropsychological tests, we used two different In our center, participants with DS are initially clinically classified approaches. The first approach consisted in defining the scores at per- by neurologists and neuropsychologists in a consensus meeting after centile ranks of 1st, 5th, and 10th in the young (age ≤ 35) asymptomatic independent visits into the following diagnostic categories: (1) asymp- DS participants in mild and moderate ID separately.24 This decision tomatic (aDS), when there is no clinical or neuropsychological suspicion was based on the fact that all subjects with DS show the characteris- of AD; (2) prodromal AD (pDS), when there is a suspicion of AD, but tic neuropathological signs of AD by the fourth decade of life. Subjects symptoms do not fulfill criteria for dementia; (3) AD dementia (dDS) >35 years were expected to have AD neuropathology and thus could in those subjects with DS with full blown dementia; and (4) uncertain, have undergone cognitive deterioration. The second approach con- including those patients with medical, pharmacological, or psychiatric sisted of using the receiver-operating characteristic (ROC) curve analy- conditions significantly interfering in cognition and/or functional level. ses. The optimal cut-point was determined using the Index of Union (IU) As mentioned previously, patients with an uncertain diagnosis were method, which is defined as the value whose sensitivity and specificity excluded from the analysis. It is important to note that to avoid circu- are the closest to the value of the area under the ROC curve and the larity, in this study we used the initial neurologist’s diagnosis blinded to absolute value of the difference between the sensitivity and specificity neuropsychological assessment. values is minimum. The criteria for optimality can change according to the aim of the study. However, as a general rule, minimizing the total misclassification rates is a good approach. With the IU method, since 2.6 Statistical analysis the difference between sensitivity and specificity values is minimum, this condition is met most of the time.25 All statistical analyses were done in R version 3.4.3. First, to assess the applicability of the tests, we analyzed the completion rates by level of ID and clinical status. Second, we compared the neuropsychologi- 3 RESULTS cal performance between clinical groups stratifying by the level of ID using an analysis of variance (ANOVA) for normal variables or Kruskal- A total of 567 adults with DS were eligible. Figure 1 shows the study Wallis for non-normal variables. Third, we studied the relationship of flow chart and the reasons for exclusion, mainly due to an uncer- the different neuropsychological tests with age. For this purpose, we tain diagnosis or incomplete neuropsychological assessment. The ini- fitted a local regression model stratified by level of ID.7 Finally, to tial samples for the CAMCOG-DS and the mCRT were composed of 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 BENEJAM ET AL . Initial sample N = 567 Excluded 48 - 40: Uncertain clinical diagnosis - 8: Previous intellectual disability level unknown N=519 CAMCOG-DS mCRT 81: Excluded due to 99: Excluded due to uncomplete neuropsychological uncomplete neuropsychological assessment assessment CAMCOG-DS mCRT Initial sample Initial sample N = 438 N = 420 95: Not able to complete the 149: Not able to complete the test due to cognitive test due to cognitive impairment impairment CAMCOG-DS mCRT Final sample Final sample 343 271 FIGURE 1 Study flow chart. mCRT, modified Cued Recall Test; CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down’s Syndrome 438 and 420 subjects, respectively. Of note, age and level of ID differed Overall, of the 438 subjects from the initial CAMCOG-DS sample, between those subjects included and excluded from the study. Subjects 343 (78.3%) subjects were able to complete the test. Completion rates who did not attend the neuropsychological visit were older and had were lower for the mCRT, where 271 of 420 subjects (64.5%) could more severe levels of ID (P < .05). Demographic and clinical character- complete the task. All subjects with mild ID, regardless of clinical diag- istics of participants from the CAMCOG-DS and mCRT initial sample nosis, completed the tests, as did the majority of asymptomatic and are shown in the Appendix. prodromal AD subjects with moderate levels of ID. Completion rates As expected, participants with prodromal AD and AD demen- were lower in those with pDS and dDS than in aDS. None of the subjects tia were older and had worse scores than asymptomatic subjects with profound ID and only a few subjects with severe ID were able to on the DLD (P < .001). There were no differences in the number complete the tests. Therefore, subjects with severe and profound lev- of men and women between the groups. There was a higher pro- els of ID were excluded from the subsequent analyses (normative data portion of subjects with severe/profound ID in the group with AD and ROC analysis). dementia. 3.2 Cognitive performance with aging and along the 3.1 Completion rates by level of ID and clinical AD continuum by level of ID diagnosis Median scores and interquartile range for the cognitive and functional Figure 2 shows the CAMCOG-DS and mCRT completion rates by level tests in those who completed the tests are presented in Table 1. Partic- of ID and clinical diagnosis. The most common reasons for not complet- ipants with mild ID obtained higher scores on the CAMCOG-DS than ing the test were not understanding the task and/or test instructions subjects with moderate ID in the whole AD continuum (median scores and/or severe attentional difficulties. in aDS: 89 vs 75, P < .0001; pDS: 79 vs 60.5, P = .0013; dDS: 76.5 vs 55, 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BENEJAM ET AL . 5 of 10 F I G U R E 2 Completion rates for the CAMCOG-DS and mCRT by level of intellectual disability and by diagnostic group. mCRT, modified Cued Recall Test; CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down’s Syndrome; ID, intellectual disability; aDS, asymptomatic Down syndrome; pDS, prodromal Down syndrome; dDS, dementia Down syndrome P = .021) (Figure 3). Total scores on the mCRT were significantly differ- 78, and 80. In subjects with moderate ID, cut-points corresponding to ent between subjects with mild and moderate ID in aDS (median 36 vs these percentiles were as follows: 48, 53, and 59, respectively. 35, respectively, P = .0002), but not in pDS (28 vs 27, respectively, P = For the mCRT, cut-points for the participants with mild ID were 34 .92) and dDS (21 vs 15, respectively, P = .37) participants. for the 1st percentile, and 35 for the 5th and 10th percentiles. For those We found no differences between male and female participants in subjects with moderate ID, these percentiles corresponded to a score the cognitive scores. There was an age effect on CAMCOG-DS and of 30, 32, and 33, respectively. mCRT scores, both in the whole cohort and in aDS individuals (Fig- ure 4). There was a progressive decline on both the CAMCOG-DS and mCRT after age 40, and especially for the subgroup of participants with 3.4 Diagnostic performance moderate ID. To assess the diagnostic performance to detect prodromal AD and AD dementia we performed ROC curve analyses. All subjects with DS 3.3 Normative data for the CAMCOG-DS and mCRT with mild ID and a very high proportion of subjects with moderate ID in asymptomatic DS individuals were able to complete the tests. However, a subset of participants with moderate ID and symptomatic AD had difficulties understanding the To exclude preclinical AD, we derived normative data in the younger instructions of the CAMCOG-DS and/or the mCRT due to cognitive dif- subjects (≤35 years: 107 subjects for the CAMCOG-DS and 89 subjects ficulties, and thus received a score of “0” (represented in purple in Fig- for the mCRT). Normative data were generated in aDS individuals in ure 3). These subjects were excluded from these analyses due to con- mild and moderate ID separately. Scores corresponding to the 1st, 5th, cerns about construct validity. and 10th percentiles were used to define pathological performances Figure 5 shows the ROC analyses. The AUC for CAMCOG-DS for (see Appendix for further details). the aDSversus pDS comparison in mild ID was 0.81 (95% CI 0.55–1), For the CAMCOG-DS, cut-points corresponding to the 1st, 5th, and the optimal cutoff point was 82, with a sensitivity of 80% and a and 10th percentiles for subjects with mild ID were, respectively, 77, specificity of 80.5%. Comparing aDS versus dDS, we obtained an AUC 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 BENEJAM ET AL . TA B L E 1 Demographic characteristics, median scores, and interquartile range (IQR) for the cognitive and functional tests of the participants who completed the CAMCOG-DS and the mCRT CAMCOG-DS subgroup aDS pDS dDS TOTAL N 277 31 35 343 Sex (F/M) 132/145 18/13 19/16 168/174 Age (median years [IQR]) 37 [15.0] 51 [4.5] 53 [8.5] 41 [18.5] ID (Mild/Moderate/Severe+Profound) 82/159/36 5/21/5 4/25/6 91/205/47 CAMCOG-DS (median [IQR]) 78 [25.0] 58 [24.5] 45 [26.5] 73 [30.0] DLD (median [IQR]) 12 [14.0] 21[19.5] 43 [17.8] 14 [17.0] mCRT subgroup N 220 31 20 271 Sex (F/M) 101/119 17/14 10/10 128/143 Age (median years [IQR]) 36 [15.0] 51 [5.0] 54 [7.0] 39 [18.0] ID (Mild/Moderate/Severe+Profound) 75/125/20 5/23/3 5/13/2 85/161/25 mCRT (median [IQR]) 36.0 [2.0] 27.0 [16.0] 15.5 [11.3] 35.0 [4.0] DLD (median [IQR]) 11 [12.0] 17.5 [13.5] 35 [24.0] 13 [13.0] aDS, asymptomatic Down syndrome; CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down’s Syndrome; dDS, dementia Down syn- drome; DLD, Dementia Questionnaire for People with Learning Disabilities; F, female; ID, intellectual disability; IQR, interquartile range; M, male; mCRT, Modified Cued Recall Test; pDS, prodromal Down syndrome. of 0.91 (95% CI 0.78–1) and an optimal cutoff point of 80, with a sensi- diagnose symptomatic AD using population norms in people with DS tivity of 75% and a specificity of 87.8%. In the subgroup of participants through the administration of neuropsychological tests in adults with with moderate ID, the AUC in the aDS versus pDS comparison was 0.73 mild and moderate ID. The cutoff points derived from the normative (95% CI 0.63–0.83), with a cutoff point of 64, a sensitivity of 66.7%, and data were in agreement with the thresholds in the ROC analyses. a specificity of 72.3%. When comparing aDS versus dDS, we found an Completion rates for the CAMCOG-DS and mCRT greatly varied by AUC of 0.90 (95% CI 0.83–0.97) and a cutoff point of 56, with a sensi- the severity of ID and along the AD continuum, with the mCRT show- tivity of 84% and a specificity of 84.3%. ing lower completion rates. This was an expected result, as these tests In the ROC analysis for the mCRT scores (Figure 5), the AUC for were designed to assess cognition in mild and moderate ID. Virtually the comparisons between aDS and pDS with mild ID was 0.79 (95% CI all aDS with mild and moderate ID completed the tests compared to 0.38–1), with a cutoff point of 35, a sensitivity of 66.7%, and a speci- less than 50% of subjects with severe ID and none of the subjects with ficity of 73.3%. Comparing aDS versus dDS, we obtained an AUC of profound ID. Similarly, symptomatic AD also affected completion rates. 1 (95% CI 1–1), with a cutoff point of 29, a sensitivity of 100%, and a Although most pDS with mild or moderate levels of ID could complete specificity of 100%. In the subgroup of participants with moderate ID, the tests, completion rates decreased in dDS with moderate ID. These we obtained an AUC for the comparison between aDS and pDS of 0.83 results show that assessing cognition in mild to moderate ID is feasible (95% CI 0.73–0.94) and a cutoff point of 33, with a sensitivity of 78.3% along the AD continuum, but that other instruments with lower floor and a specificity of 79.2%. When comparing aDS versus dDS, we found effects should be used in severe ID. an AUC of 0.97 (95% CI 0.93–1) and a cutoff point of 28, with a sensi- The level of ID had a greater impact on CAMCOG-DS scores than tivity of 92.3% and a specificity of 94.4%. on mCRT scores. Subjects with mild ID obtained significantly higher Normative values corresponding to the 1st, 5th, and 10th per- scores on the CAMCOG-DS than subjects within the moderate range. centiles obtained in young aDS with DS were comparable to those cut- The mCRT, however, was less sensitive. As in our previous report points obtained by ROC analysis for the detection of symptomatic AD on the natural history of AD in DS, cognitive decline was detectable for both CAMCOG-DS and mCRT (Appendix, Table S2). after age 40, especially in moderate ID,7 in agreement with previous studies.26-28 The median age at diagnosis in our aforementioned study was 50.2 years for pDS and 53.7 years for dDS.7 Therefore, cognitive 4 DISCUSSION decline is detectable cross-sectionally 10 years before symptomatic AD and occurs in parallel to hippocampal atrophy,7 after amyloid and This is the first study to show the applicability of the mCRT and the tau biomarkers become abnormal. These results reinforce that most of CAMCOG-DS in a large population-based cohort stratified by level the decline associated with aging in DS is AD related. It is important to of ID, and also the first to show the diagnostic performance to detect consider that all subjects with DS show the characteristic neuropatho- prodromal AD and AD dementia. We showed that it is possible to logical signs of AD by the fourth decade of life.4,29,30 For this reason, in 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BENEJAM ET AL . 7 of 10 F I G U R E 3 Neuropsychological performance of Down syndrome by clinical groups according to level of intellectual disability. ID, intellectual disability; aDS, asymptomatic Down syndrome; pDS, prodromal Down syndrome; dDS, dementia Down syndrome; mCRT, modified Cued Recall Test. CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down’s Syndrome. A subset of participants with moderate ID had difficulties understanding the instructions of the CAMCOG-DS and/or the mCRT due to cognitive difficulties, and thus received a score of “0” on these tasks (represented in purple at the bottom of the figure) F I G U R E 4 Relationship between age and cognitive scores in subjects with mild and moderate ID for the whole cohort. Footnote: mCRT, modified Cued Recall Test; CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down’s Syndrome; ID, intellectual disability; DS, Down syndrome order to derive the population norms, we chose the younger individuals erate ID. Prodromal AD could also be diagnosed with good accuracy (≤35 years). in mild ID, but not in moderate levels of ID. The mCRT showed higher There was a clear decrease in both the CAMCOG-DS and mCRT val- diagnostic performance than the CAMCOG-DS. To the best of our ues along the AD continuum. ROC analyses showed good diagnostic knowledge, only one group has reported on CAMCOG-DS cutoff performance for the CAMCOG-DS and the mCRT. The cutoff score for scores for the diagnoses of AD dementia in people with DS.22 In the val- the CAMCOG-DS derived from the ROC analyses achieved high sensi- idation study of the CAMDEX-DS in Spain, Esteba et al. found a cutoff tivity and specificity to diagnose AD dementia in both mild and mod- score of 68 in mild ID and 52 in moderate ID,22 lower than in our study 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 BENEJAM ET AL . F I G U R E 5 ROC curve analysis of diagnostic performance of CAMCOG-DS total score (a) and the mCRT total immediate recall score (b) for Down syndrome clinical groups (prodromal DS and dementia DS). pDS, prodromal Down syndrome; dDS, dementia Down syndrome; mCRT, modified Cued Recall Test; CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down’s Syndrome; ID, intellectual disability (we obtained cutoff scores of 80 and 56, respectively). The inclusion of 29 and 28 (for the mild and moderate level of ID, respectively), of subjects with less cognitive decline in our study, which is based on a derived from the ROC analyses, are higher than that reported by population health plan with active screening for AD, might explain the Devenny et al.,18 who proposed a provisional cutoff score of 23 to iden- discrepancies. Cued recall tasks31 are commonly used in the general tify dementia due to AD in DS populations.18 Similar to the CAMCOG- population to differentiate between memory decline related to aging DS results, these differences could be explained by the inclusion in our and AD-related memory deficits.32,33 aDS individuals often performed sample of subjects with earlier stages of AD, and thus with less impair- at ceiling on the total score of the test. It is notable that this test was ment in memory functions. less sensitive to the level of ID than the CAMCOG-DS, and the cut- We provide several thresholds for the normative data for the offs were very similar in the mild and moderate levels of ID. This lower CAMCOG-DS and the mCRT obtained in younger asymptomatic variability associated to the level of ID facilitates diagnosis. Cognitive subjects with DS (aged ≤ 35 years) with mild and moderate levels of ID functions have been shown to decline sequentially in people with DS, (1st, 5th, and 10th percentiles). These cutoffs were in agreement with with different cognitive domains being affected at different stages of those established for the diagnosis of prodromal AD and AD dementia the disease.15,34,35 A longitudinal study conducted by Krinsky-McHale using ROC analyses (with the exception of the mCRT cutoffs derived et al.36 found that participants with DS with early stage AD dementia in the ROC analyses for AD dementia). CAMCOG-DS scores below 80 showed severely diminished episodic memory. Again, our cutoff scores in subjects with mild ID and below 59 in those with moderate ID were 23528729, 2020, 1, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12047 by Readcube (Labtiva Inc.), Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BENEJAM ET AL . 9 of 10 indicative of a pathological performance on this test (corresponding to This study was supported by the Fondo de Investigaciones Sani- the 10th percentile). In the case of the mCRT, total immediate scores tario (FIS), Instituto de Salud Carlos III (PI14/01126 and PI17/01019 to below 35 and 33 for those subjects with mild and moderate ID, respec- Juan Fortea, PI13/01532 and PI16/01825 to Rafael Blesa, PI18/00335 tively, could be considered at risk for symptomatic AD (both prodromal to Maria Carmona-Iragui, INT19/00016 and PI18/00435 to Daniel AD and AD dementia). Therefore, the 10th percentile cutoffs could be Alcolea, and PI14/1561 and PI17/01896 to Alberto Lleó) and the used for screening purposes in clinical practice. However, to diagnose CIBERNED program (Program 1, Alzheimer Disease to Alberto Lleó AD dementia, more stringent thresholds should be used, especially for and SIGNAL study, www.signalstudy.es), partly jointly funded by Fondo the CRT. Europeo de Desarrollo Regional, Unión Europea, Una manera de Taking into account the sensitivity and specificity obtained in both hacer Europa. This work was also supported by the National Insti- the normative data and from the ROC curve analysis, the cutoff points tutes of Health (NIA grants 1R01AG056850–01A1; R21AG056974 that we would recommend for the diagnosis of AD dementia in people and R01AG061566 to Juan Fortea), Departament de Salut de la with DS would be the following: In mild ID, CAMCOG-DS scores of 80 Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en and mCRT scores of 29; in moderate ID, CAMCOG-DS scores of 56 and Salut (SLT002/16/00408 to Alberto Lleó), Fundació La Marató de TV3 mCRT scores of 28. (20141210 to Juan Fortea and 044412 to Rafael Blesa); Fundació Cata- The main strengths of this study are the large sample size and the lana Síndrome de Down and Fundació Víctor Grífols i Lucas partially fact that it comes from a large population-based cohort of adults with supported this work. This work was also supported by Generalitat de DS representative of the DS population in Catalonia. This enabled us to Catalunya (SLT006/17/00119 to Juan Fortea, SLT006/17/95 to Eduard establish robust population-based norms in young aDS stratified by the Vilaplana and SLT006/17/00125 to Daniel Alcolea) and a grant from level of ID. Another strength is that we could compare the thresholds the Fundació Bancaria La Caixa to Rafael Blesa. derived from this approach to those of the ROC analyses, showing The article describes independent research, and the views that the thresholds were comparable and yielded good diagnostic expressed are those of the authors and not necessarily those of performance. This study also has some limitations. First, it is based the funders. The sponsors of the study did not take part in the design on cross-sectional data. Second, it is a single-center study, and thus and conduct of the study; collection, management, analysis, and inter- needs to be replicated in other cohorts and populations to confirm the pretation of the data; writing and review of the report; or the decision generalizability of our results. Third, despite the large overall sample to submit the article for publication. size, the number of subjects with prodromal AD and AD dementia with mild ID was reduced. For this reason we did not perform an internal CONFLICTS OF INTEREST cross-validation in the ROC approach. Fourth, to avoid circularity, we Dr. Fortea has received compensation for consultancies to Novartis used the neurologist’s initial diagnosis, blinded to neuropsychological and AC Immune. The remaining authors have no conflicts of interest assessment, and this could have led to a misidentification of prodromal to declare that are relevant for this article. AD cases as asymptomatic or to the inclusion in the asymptomatic group of subjects with medical, pharmacological, or psychiatric con- ORCID ditions that could have effects on cognition not detected by the Juan Fortea https://orcid.org/0000-0002-1340-638X neurologist. Of note this might have underestimated the diagnostic performance of the tests. Further studies with longitudinal follow-up and/or biomarkers would allow for more reliable diagnosis.37 REFERENCES In summary, our study shows that, similar to the general population, 1. McCarron M, McCallion P, Reilly E, Mulryan N. A prospective 14-year a diagnosis of prodromal AD and AD dementia can be done reliably in longitudinal follow-up of dementia in persons with Down syndrome. 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