ORIGINAL RESEARCH published: 30 March 2022 doi: 10.3389/fnins.2022.838412 Feasibility and Long-Term Compliance to Continuous Positive Airway Pressure Treatment in Adults With Down Syndrome, a Genetic Form of Alzheimer’s Disease Sandra Giménez 1* , Ariadna Farre 1 , Fátima Morente 1 , Laura Videla 2,3,4 , Marta Gutiérrez 1 , Susana Clos 2 , Ana Fernández 1 , Marta Blanco 1 , Miren Altuna 2,3 , Jordi Pegueroles 2 , Amparo Asensio 1 , Bessy Benejam 2,3,4 , Mar Batista 1 , Isabel Barroeta 2,3 , Ana Fortuna 1 , Juan Fortea 2,3,4 and Mercedes Mayos 1,5 1 Multidisciplinary Sleep Unit, Respiratory Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Barcelona, Spain, 2 Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Edited by: Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Center of Biomedical Gerard Piñol-Ripoll, Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain, 4 Barcelona Down Medical Center, Hospital Universitari de Santa Maria, Fundació Catalana de Síndrome de Down, Barcelona, Spain, 5 Centro de Investigación Biomédica en Red de Enfermedades Spain Respiratorias (CIBERNED), Madrid, Spain Reviewed by: Maria Bonsignore, University of Palermo, Italy Background: Down syndrome (DS) is a genetic form of Alzheimer’s disease (AD) with Michelangelo Maestri, a high prevalence of obstructive sleep apnea (OSA). These characteristics place the DS University of Pisa, Italy population as an optimal model to study the relationship between sleep and AD and *Correspondence: Sandra Giménez to design clinical trials of preventive sleep therapies for AD. Regrettably, OSA treatment sgimenez@santpau.cat with continuous positive airway pressure (CPAP) is often neglected in adults with DS. In both clinical practice and research trials, it is usually presumed that these patients will Specialty section: This article was submitted to not adapt to or tolerate the therapy. Sleep and Circadian Rhythms, a section of the journal Study Objective: We aimed to evaluate the feasibility and long-term CPAP compliance Frontiers in Neuroscience in this population and their capacity to be enrolled in CPAP research studies. Received: 17 December 2021 Methods: We prospectively compared the CPAP compliance of 17 OSA patients with Accepted: 15 February 2022 Published: 30 March 2022 DS and 19 age and sex matched OSA euploid patients. CPAP management and follow- Citation: up schedules were prescribed according to the habitual clinical practice. We compared Giménez S, Farre A, Morente F, group differences in tolerance, objective, and subjective hours of nightly CPAP usage at Videla L, Gutiérrez M, Clos S, Fernández A, Blanco M, Altuna M, the 1st, 3rd, 6th, 12th, 24th, and 36th month visits. Good compliance was defined Pegueroles J, Asensio A, Benejam B, as at least 4 h use per night. We also investigated predictive factors of long-term Batista M, Barroeta I, Fortuna A, CPAP compliance. Fortea J and Mayos M (2022) Feasibility and Long-Term Results: The percentage of DS subjects with good CPAP compliance (81.2 vs. 78.9%) Compliance to Continuous Positive Airway Pressure Treatment in Adults and the objective CPAP use (5 vs. 6 h, p = 0.92) did not differ from the control group With Down Syndrome, a Genetic (CG). Subjective CPAP compliance was significantly higher in OSA patients with DS Form of Alzheimer’s Disease. Front. Neurosci. 16:838412. than in controls in all the follow-up visits (8 vs. 6.75 h, p = 0.001). The DS group had a doi: 10.3389/fnins.2022.838412 significantly higher number of visits (9 vs. 5; p = 0.021) and mask changes (2.5 vs. 2; Frontiers in Neuroscience | www.frontiersin.org 1 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS p = 0.05) than controls. Objective hours of CPAP use at the first follow-up visit predicted long-term CPAP compliance (p < 0.005). Conclusion: CPAP treatment is feasible and has good long-term compliance in OSA patients with DS. It should be recommended to improve health and prevent comorbidities. The DS population is indeed suitable to participate in longitudinal preventive sleep clinical trials for AD. Keywords: obstructive sleep apnea, CPAP compliance, Down syndrome, Alzheimer’s disease, sleep INTRODUCTION AD diagnosis (Osorio et al., 2015; Liguori et al., 2017). Further OSA longitudinal studies examining the possible protective Down syndrome (DS) is a genetic form of Alzheimer’s disease effect of CPAP treatment on AD biomarkers in the preclinical (AD) with a long and predictable preclinical phase similar to that stages of AD are required to study the relationship between in the sporadic and autosomal dominant form (Fortea et al., 2020, OSA and AD (Liguori et al., 2021). To advance in this 2021). The triplication of the amyloid precursor protein (APP) knowledge, it has been suggested that further complementary located in chromosome 21 increases the production of amyloid research should move into different populations and on to beta (Aβ). The lifetime risk for early-onset Alzheimer’s disease is phase III clinical trials (Bubu et al., 2020; Mullins et al., over 90% (Ballard et al., 2016). 2020). The extra copy of chromosome 21 is also associated In the population with DS, as in the general population, OSA with several morphological and functional abnormalities, that may impair cognitive function and accelerate the progression among others narrow the upper airway and predispose the to AD dementia (Cody et al., 2019; Giménez et al., 2021). The DS population to obstructive sleep apnea (OSA) from infancy elevated risk of both AD and OSA in adults with DS makes (Simson et al., 2018). With aging, this risk increases, partly this population ideally an optimal model not only to study this due to the development of hypothyroidism and obesity (Lal relationship, but also to conduct clinical trials of preventive sleep et al., 2015). The prevalence of OSA in adults with DS ranges therapies for AD. between 65 and 89% (Trois et al., 2009; Giménez et al., 2018, Obstructive sleep apnea treatment with CPAP, however, is 2021; Landete et al., 2020), which represents that OSA is at least not usually proposed in adults with DS. Both caregivers and five times more common in DS than in the general population physicians often presume that these patients will not tolerate (Heinzer et al., 2015). CPAP and that additional complex interventions are needed to Obstructive sleep apnea is a sleep breathing disorder ensure compliance with the treatment. This may be reinforced characterized by episodes of upper airway occlusion, that by the limited data about CPAP treatment in adults with OSA entails chronic intermittent hypoxemia, hypercapnia, metabolic and DS, and by the absence of objective studies evaluating the abnormalities, sleep fragmentation, and cerebral hypoperfusion feasibility, efficacy, and long-term compliance of CPAP therapy (Lévy et al., 2015). OSA is independently associated with in this population (Hill et al., 2020; Landete et al., 2020). excessive daytime sleepiness, cognitive impairment, depression, In this study we aimed to evaluate the feasibility and long- cardiovascular disease, and all-cause mortality (Gottlieb term compliance of CPAP treatment in adults with OSA and and Punjabi, 2020). Indeed, increasing evidence supports a DS when using the same clinical protocol of CPAP management pathophysiological relationship between OSA and Alzheimer’s routinely used in the general population. We also investigated the disease, as demonstrated by links between mentioned mediating predictive factors associated with long-term CPAP compliance. OSA factors and AD biomarkers of neurodegeneration (Sharma et al., 2018; Bubu et al., 2019, 2020). Whereas AD does not yet have an effective treatment, some MATERIALS AND METHODS of the pathologic mechanisms in OSA can be reverted by OSA treatment helping to prevent cognitive decline (Mullins et al., Study Population 2020). OSA, thus, may be an important modifiable risk factor Neuroimaging Initiative (DABNI), a research health program for AD prevention. to screen for Alzheimer’s dementia (AD) in adults with DS Continuous positive airway pressure (CPAP) is considered the that includes a complete sleep study (Alcolea et al., 2019). The first line treatment for OSA (Patil et al., 2019). In the general patient’s characteristics and the sleep study protocol procedures population CPAP reduces sleepiness, the risk of cardiovascular and results have been described in detail elsewhere (Giménez comorbidities, and improves daytime functioning (Marin et al., et al., 2018). Briefly, between September 2014 and June 2016, 47 2005). In patients with mild cognitive impairment and AD, community-based participants with DS not selected or referred CPAP treatment also improved cognition and delayed the age of for sleep disorders underwent a polysomnography (PSG), of whom 78% had OSA. For the present CPAP compliance Abbreviations: DS, Down syndrome; AD, Alzheimer’s disease; PSG, nocturnal polysomnography; AHI, apnea–hypopnea index; OSA, obstructive sleep apnea; study, we prospectively collected follow-up data from those DS CPAP, continuous positive airway pressure; ESS, Epworth Sleepiness Scale. participants with OSA and in whom CPAP therapy was proposed. Frontiers in Neuroscience | www.frontiersin.org 2 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS Indications of CPAP treatment were based on clinical criteria were also addressed and changed, if necessary. The autonomy was (Lloberes et al., 2011). checked by asking the patient to put the mask on and to turn the We also retrospectively recruited a control group (CG) of device on. In each follow-up visit, the importance of the CPAP use 19 euploid OSA patients from the general population treated was reinforced, and patients were encouraged to keep the mask with CPAP and matched for age, sex, and body mass index on every sleeping hour. (BMI) with the DS group. The study was performed in the The CG followed the same protocol, except for CPAP titration, multidisciplinary Sleep Unit of the Hospital of Sant Pau in which was performed by conventional PSG or automatic CPAP Barcelona, in collaboration with the Alzheimer Down Unit at in the sleep lab or at home following a validated protocol (Masa the same hospital. The local ethics committee following the et al., 2004). The CPAP explanatory brochure, with a user manual principles stated approved the study in accordance with the and a telephone contact number with the CPAP specialist nurse, Declaration of Helsinki. Written informed consent was obtained was also provided to the control participants. from all participants and from legal caregivers with agreement from the DS participants. Data Collection/Endpoints All data were obtained according to good clinical practice We collected baseline clinical and demographic data in (GCP) guidelines. all patients. Compliance CPAP variables were systematically recorded prospectively including: Procedures -Objective CPAP compliance: Hours of nightly usage at Continuous positive airway pressure was prescribed following months 1, 3, 6, 12, 24, and 36 months after CPAP initiation the same routine procedures that are conducted in our sleep was obtained by reading the time-counter of the CPAP unit for OSA patients. These include accurate pressure setting, device. The download data at each visit corresponds to patient education, and regular follow-up visits. Any additional the average usage in the preceding time interval since the CPAP intervention was introduced for DS patients. Briefly, previous visit. The primary outcome variable in this study after diagnosis of OSA, all patients had a consultation where was the number of hours of CPAP nightly use at follow- the sleep physician explained OSA and its consequences up and was calculated through two variables: hours of including the indication, rationale, and potential benefits of OSA CPAP usage at last visit and average hours of CPAP use treatment with CPAP, and the need to perform another PSG across all visits. Good compliance to the CPAP treatment for CPAP titration. was considered as use of CPAP >4 h per night, and non- Continuous Positive Airway Pressure Titration compliance was considered as use of CPAP ≤4 h of use per With the intention of optimizing treatment tolerance, CPAP night (Patil et al., 2019). adaptation was performed in the same day of in-hospital PSG - Subjective CPAP compliance: Estimated as the nightly titration. In the presence of the caregiver, qualified technical staff number of hours of CPAP use as reported by the patients (or explained to the patient in detail the indication, objectives, and by the caregivers in the case of DS patients), at each follow- potential discomfort that may be experienced during the titration. up visit. Final subjective compliance was calculated as the The patient was accommodated in bed, and the most reported number of hours of CPAP nightly use at follow- appropriate and comfortable facemask was chosen for each up and was also calculated through two variables: reported case according to facial morphology. When the patient felt hours of CPAP usage at last visit and reported average hours comfortable, low-pressured air was started (at 4 cmH2 O) and of CPAP use across all visits. slowly increased to medium pressures. The patients were then invited to try to nap for about 30 min. After completing this -Tolerance parameters concerning the degree of comfort procedure, the patients were subjected to the titration study with the mask, the presence of any side effects, such that same night. All patients underwent a night-time CPAP as nasal stuffiness, skin irritation, or eye puffiness titration using conventional PSG at the sleep unit with manual were systematically recorded. Any concern with the titration, according to the American Academy of Sleep Medicine interface and/or CPAP device were also addressed and recommendations (Kushida et al., 2008). In the morning, before changed if necessary. leaving, an explanatory CPAP brochure was given to the -The degree of autonomy of the patient using the CPAP caregivers, which included a user manual and a telephone contact device was noted as high if the patient could put on number with the CPAP specialist nurse. and remove the mask alone, and low if the CPAP mask assistance from caregivers was always required. Continuous Positive Airway Pressure Follow up Visits After CPAP prescription, all patients attended follow-up CPAP Dropouts were defined as patients who were prescribed CPAP visits conducted by an experienced CPAP specialist. The CPAP but never started the treatment and/or never attended the follow- follow-up visits were carried out as performed in our clinical up visits. practice: at months 1, 3, 6, and 12, and then annually or whenever The total number of additional visits within the planned required by the patient or caregivers. At each follow-up visit, interval schedule was also included. We assessed the factors compliance, tolerance, and autonomy with the CPAP device were associated with objective CPAP compliance at the end of checked. Any concerns with the interface and/or CPAP device the follow up period, including: (1) socio-demographic Frontiers in Neuroscience | www.frontiersin.org 3 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS TABLE 1 | The demographic and baseline characteristics of OSA patients with TABLE 2 | Continuous positive airway pressure follow up measurements. Down syndrome and OSA patients from the control group. DS patients (n = 16) Control patients (n = 19) p-value DS patients (n = 17) Control patients (n = 19) p-value Objective CPAP 5.00 (4.00–7.25) 6.00 (5.0–6.0) 0.920 Age (years) 45.0 (35.0–52.0) 47.0 (40.5–51.0) 0.861 use (last visit) Female, n (%) 5 (29.4) 4 (21.1) 0.847 Objective CPAP 4.86 (4.00–6.65) 5.17 (4.40–5.90) 0.934 BMI (kg/m2 ) 32.5 (28.2–34.6) 33.4 (30.35–35.75) 0.228 use (average) ESS 7.0 (4.0–13.0) 12.0 (7.0–16.0) 0.131 Subjective 8.0 (7.75–9.00) 7.00 (6.50–7.0) 0.001 CPAP use (last AHI (events/h) 48.7 (36.5–74.4) 63.0 (36.5–65.65) 0.788 visit) CPAP pressure 8.0 (7.0–9.0) 9.0 (7.5–10.0) 0.192 Subjective 8.0 (7.12–8.50) 6.75 (6.12–7.0) 0.001 (cmH2 0) CPAP use Hypertension n (%) 0 (0) 5 (26.3) 0.072 (average) Dyslipidemia 0 (0) 4 (21.1) 0.140 Good 13.0 (81.2) 15.0 (78.9) 1.00 Diabetes mellitus 1 (5.9) 3 (15.8) 0.680 compliance (%) Cardiopathy n (%) 5 (29.4) 2 (10.5) 0.314 Follow up 37 (29.7–39.0) 25.0 (1.5–34.0) 0.123 (months) Descriptive data are presented as n: number of subjects (percentages) or median and interquartile range (IQR). Number of 9.0 (7.0–13.0) 5.0 (4.0–7.70) 0.021 DS, Down syndrome; BMI, body mass index; ESS, Epworth Sleepiness Scale; AHI, visits apnea–hypopnea index; CPAP, continuous positive airway pressure. Number of 2.50 (1.75–4.0) 2.0 (0.5–2.0) 0.050 mask changes characteristics of the patients: age, gender, level of intellectual Descriptive data are presented as n: number of subjects (percentages) or median disability or social support, (2) baseline OSA severity: apnea– and interquartile range (IQR). CPAP, continuous positive airway pressure. hypopnea index (AHI), cumulative time percentage with Spo2 <90% (CT90), severity of somnolence measured by Epworth Sleepiness Scale (ESS), (3) CPAP variables: CPAP pressure, The demographic characteristics of OSA patients with DS and interface type (nasal, oronasal, or nasal pillows), number of visits, the CG are summarized in Table 1. In the DS group, median age side effects, and number of mask changes. was 45 years (range 35–52), the majority were men (12, 70.6%), Statistical Analyses and had severe OSA (14, 82.3%). Only three had moderate OSA (17.65%). There were no differences in age, sex, BMI, daytime Demographic characteristics were summarized using the median somnolence (ESS), and AHI or CPAP pressure between OSA and interquantile range (IQR) for continuous variables and patients with DS and the CG. Five control subjects had a history percentages for categorical variables. Mann–Whitney test was of hypertension (HTA), but none in the DS group. used to test differences between groups. Additionally, Cliff ’s At the end of the study period, no significant differences delta was computed to test the effect size between groups. To were observed in the median objective CPAP use between test the evolution of CPAP compliance between groups over groups (Table 2). Thirteen DS patients (81.2%) had good time we performed linear mixed-effects (LMEs) models using CPAP compliance. From the three non-compliant OSA patients the maximum likelihood method for the change in CPAP over with DS, one patient remained on CPAP therapy although time. We included age, sex, group, time from baseline, and insufficiently, and two patients dropped out after 1 month. In the interaction between time and group as fixed effects and the CG, all patients started CPAP treatment and 15 patients intercept and time from baseline were included as subject- (78.95%) had good compliance. From the four non-compliant specific random effects. participants, one patient dropped out after the first follow-up Continuous positive airway pressure predictive factors were visit. There was no difference in hours of CPAP use between the evaluated by Spearman’s rank correlation analyses. The time DS group (5.60 h, range 4.50–6.80) and controls (5.67 h, range to achieve good compliance was taken as the visit that was 4.92–6.00) within the subgroup of good compliance patients significantly above the compliance threshold. All plots and (p = 0.963). In the CG there were no significant differences in statistical analyses were performed using R statistical software the average of objective CPAP compliance (p = 0.96) neither in (v 3.6.3). A p-value of less than 0.05 was considered statistically subjective CPAP compliance (z = 0.206) between patients with significant and a Cliff ’s delta (d) of more than 0.47 was considered and without hypertension. a large effect size. When assessing the LMEs analysis, in both groups, the duration of objective CPAP use increased gradually in the follow- RESULTS up (results from the LME analyses are shown in Supplementary Table 1). In OSA patients with DS, there was a significant Continuous positive airway pressure treatment was proposed for increase in CPAP use from the first month visit (4 h, range 17 patients with DS during the study period. All accepted and 0.82–6.25) compared to the 24-month visit (7 h, range 5.50– completed a PSG and CPAP titration in the hospital. One OSA 7.50, p = 0.05) and between the first and the 36-month patient with DS refused to start CPAP treatment and dropped out visit (6 h, range 5.0–8, p = 0.05) (Figure 1A). In OSA before the first follow-up visit. patients with DS good CPAP compliance was achieved after Frontiers in Neuroscience | www.frontiersin.org 4 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS FIGURE 1 | Objective and subjective CPAP compliance follow up in OSA patients with OS and CG. DS, Down syndrome; CG, control group; CPAP, continuous positive airway pressure; m, month. Objective and subjective trajectory of CPAP compliance is represented by the mean (+SE) nightly CPAP use at each follow up visits (1–36 months). ∗ Significant differences (p < 0.05) in CPAP use across visits (A), and between groups (B) are indicated. 3 months of treatment. No significant differences in CPAP use In the DS group, better CPAP compliance was not significantly among visits were observed in the control patients. There was but was nominally associated with a major number of visits no significant difference in CPAP use across visits between (p = 0.28; d = 0.41) and higher Epworth scores (p = 0.2; d = 0.56). DS and controls. In the CG, an increased number of visits (p = 0.03; d = 0.7), At the end of the study period, the percentage of subjects with an absence of cardiopathy (p = 0.048; d = 0.5), a higher baseline good CPAP compliance was comparable in both groups. There CT90 (p = 0.044; d = 0.53), and a trend for an association with was a tendency toward a lower frequency of compliance in the DS higher IAH (p = 0.06; d = 0.62) were associated with better long- group compared to the controls (56 vs. 86%, p = 0.084) in the first term CPAP compliance. month follow-up visit only. In the DS group a tendency toward increased compliance was observed between the 1-month and 3- month visits (56 vs. 86%, p = 0.089), and between the 1-month DISCUSSION and both 24- and 36-month visits (56 vs. 90%, p = 0.061). In average, subjective CPAP use was higher than the objective This study shows that CPAP for OSA treatment is feasible use in both groups (Figure 2). OSA patients with DS reported in adults with Down syndrome, with good and long-term significantly higher subjective compliance compared to control compliance applying the same clinical practice of CPAP participants, on the average CPAP use at the end of the study management than in the general population. Besides the clinical period (Table 2), and in every follow up visit, except the first relevance of the data, it also demonstrates the capacity of adults month follow up visit. In both groups, a good CPAP compliance with DS to participate in CPAP clinical research studies. was already reported from the first follow up visit (Figure 1B). Four hours cut-off point is the most accepted criterion There were no changes in subjective CPAP use across visits in the to differentiate between bad and good compliance to CPAP follow-up period in the DS group or in the CG. treatment (Patil et al., 2019). In the general population, the Obstructive sleep apnea patients with DS had a significantly percentage of good CPAP compliance ranges from 28 to 83% higher median number of visits compared to the CG (Table 2). (Sawyer et al., 2011), with higher rates at the beginning of the Fourteen OSA patients with DS (87.5%) used a nasal mask treatment (Mehrtash et al., 2019), and decreases in adherence in and 2 an oronasal mask. The most common side effects were longer follow-up periods (Rotenberg et al., 2016; Cistulli et al., due to problems with the interface (93.75%) and nasal congestion 2019). In the present study, CPAP compliance in OSA adults with (25%). The number of mask changes was significantly increased DS was lower in the first month, but gradually and significantly in patients with DS vs. controls. Four patients (25%) were highly increased from the first to the last visit, in contrast to controls autonomous in the management of CPAP, others needed help (Rotenberg et al., 2016; Baratta et al., 2018; Cistulli et al., 2019). from their caregivers. Only one OSA patients with DS lived in After 3 years of follow-up, 81% of OSA patients with DS were a group home and did not show good compliance. considered to have good CPAP compliance, with nightly CPAP Objective hours of CPAP use at the first follow-up visit were use of 5 h, a compliance that is comparable to that of the CG. the only predictive factors of good CPAP compliance at 3 years There are scarce and heterogeneous data in the literature for both the DS (p < 0.001, rho = 0.78) and control (p = 0.004, relating to the suitability of CPAP treatment in adults with rho = 0.71) groups. DS. Good CPAP compliance has been reported in 62.5% of Frontiers in Neuroscience | www.frontiersin.org 5 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS FIGURE 2 | Objective and subjective CPAP use in OSA patients with DS and CG. DS, Down syndrome; CG, control group; CPAP, continuous positive airway pressure. Boxplots illustrate the distribution of nightly CPAP use showing the individual data points and the median average use. ∗ Significant differences (p < 0.05) between groups are indicated. subjects with DS after 1 year of treatment (Trois et al., 2009), (Shapiro and Shapiro, 2010; Luijks et al., 2017). In subjects in 60% of subjects after an intensive 6 months of CPAP with DS, the management and supervision of CPAP depends training protocol (Weaver and Grunstein, 2008), and in 79% mainly on OSA education and motivation of their caregivers. of adults with DS symptomatic for OSA (Landete et al., 2020). Caregivers were concerned that the effectiveness of the therapy Insufficient CPAP compliance was reported in a prospective relies on CPAP acceptance and compliance (Griffin et al., 2013; CPAP randomized study after 1 year of follow-up (Hill et al., Luijks et al., 2017), and early side effects and troubleshooting 2020). In most of these studies, however, methodological data were quickly communicated during the follow-up period. regarding compliance or follow-up measurements were not OSA patients with DS, probably due to their narrow nasal provided. Our study substantially differs from the above studies passages, presented more mask discomfort, that resulted in more and adds important new data: (1) participants followed the mask changes than in controls (Aloia et al., 2005). Additional habitual clinical practice of CPAP management in our sleep follow-up visits to correct these issues resulted in increased unit, (2) the study included substantially longer follow-up with CPAP compliance (Aloia et al., 2005; Griffin et al., 2013). a detailed trajectory of CPAP use, (3) an additional comparison Another finding of our study regarding caregivers is that they between subjective and objective data was assessed, (4) inclusion overestimated subjective CPAP use more than the discrepancy of control OSA patients from the general population that had reported in the general population (Rauscher et al., 1993). This the same clinical follow-up protocol, (5) factors predicting CPAP misperception was already present in the first visit, despite compliance were explored, and (6) the study was not subject insufficient objective compliance in this period, but contributed to selection bias since our patients were not selected due to to their favorable opinion of the treatment. sleep complaints. Our results are clinically relevant as they provide evidence that We investigated several patient, sociodemographic, and CPAP treatment is not only feasible in OSA adults with DS, but disease factors that have been assessed in relation to CPAP also perfectly integrated in patients and caregivers’ routines, and compliance (Shapiro and Shapiro, 2010; Sawyer et al., 2011; can be sustained for extended periods without major changes. Luijks et al., 2017; Gottlieb and Punjabi, 2020). Disease factors, such as baseline OSA severity and excessive In the general population, the patient’s perception of daytime somnolence (ESD), were not associated with better OSA symptoms, risks, benefits of the therapy, and measures long-term CPAP compliance in OSA patients with DS, in of self-efficacy increase self-motivation to CPAP use contrast to controls. In the general population, it is likely Frontiers in Neuroscience | www.frontiersin.org 6 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS that the relief of these OSA symptoms increases motivation sample size, which may have limited the power to establish to endure treatment (Griffin et al., 2013; Jacobsen et al., significant differences in some variables. Most of the participants 2017), despite data being inconclusive (Kohler et al., 2010). were middle-aged adults. Outside these ages ranges, results In the intellectual disability population, it has been proposed in CPAP compliance may differ. DS participants came from that other disease factors, such as improvement in sleep a population-based health plan design to screen for AD in quality, may in part explain the high CPAP tolerance observed DS, reflecting the population of adults with DS in Catalonia (Campos-Rodriguez et al., 2005; Weaver and Grunstein, 2008). and the CG was recruited during clinical practice at a sleep CPAP compliance may vary with age, with younger subjects clinic. This might have increased the motivation to CPAP presenting worse compliance (Kang et al., 2019; Giménez treatment in the controls, but despite this fact, CPAP compliance et al., 2021). Maybe middle-aged patients actually represent in the DS population was comparable. Moreover, due to the milder end of the OSA severity spectrum, with better the small sample size and the variable levels of intellectual CPAP compliance. On the other hand, most adults with DS disability associated with DS, changes in cognitive function present OSA already from infancy, which could lead to a after CPAP treatment could not be provided. Further larger progressive clinical adaptation to adverse symptomatology of studies are needed to assess the efficacy of CPAP treatment in chronic OSA. Further polysomnography sleep studies are needed this population. to evaluate objective sleep changes after CPAP treatment to In conclusion, our study showed that CPAP treatment is assess improvements in sleep quality and their relation to CPAP feasible in OSA adults with DS, and with a good long follow-up compliance across ages. compliance when adhering to the usual clinical practice of CPAP Objective hours of CPAP use at the first follow-up was the only management that is applied to the general population. predictor of long-term use in both groups, thus highlighting the These data underlie that OSA treatment should be importance of early CPAP compliance in the DS population, as recommended and might prevent comorbidities and improve has been reported in the general population (Kang et al., 2019; the quality of life in this vulnerable population. It also highlights Mehrtash et al., 2019). This is extremely important since, contrary the capability and willingness of adults with Down syndrome to the general population, CPAP treatment in the DS population to participate in CPAP research studies of preventive sleep is not habitually initiated to treat acute OSA symptoms to prevent therapies for AD. cardiovascular problems or to reduce risk of accidents and, therefore, the perception of the urgency and the need for CPAP treatment can be low (Weaver and Grunstein, 2008). DISCLOSURE Life expectancy in the population with DS has increased, and accordingly, comorbidities associated with aging, such as OSA Work for this study was performed at Santa Creu i Sant Pau and Alzheimer’s disease. Further studies are need to determine University Hospital in Barcelona. All co-authors have reviewed the efficacy of CPAP treatment in minimized additional cognitive and agreed on the contents of the manuscript and there is no impact and decelerate the progression to symptomatic (Lal financial interest to report. et al., 2015; Simson et al., 2018). Unfortunately, adults with Down syndrome have not been included in preventive AD clinical trials. Ethic challenges and concerns about the feasibility DATA AVAILABILITY STATEMENT of completing all assessments compared with those done in The raw data supporting the conclusions of this article will be the general population are the main reasons. Luckily, the made available by the authors, without undue reservation. exponential increasing research in AD in the DS population is rapidly reversing this scenario (Hendrix et al., 2020; Fortea et al., 2021). Briefly, the Down syndrome population has (1) ETHICS STATEMENT an ultra-high risk for developing symptomatic Alzheimer’s disease with a long preclinical phase in which biomarkers The studies involving human participants were reviewed and follow a predictable order of changes over more than 2 approved by the Clinical Research Ethics Committee (CEIC), decades, (2) a high OSA prevalence, (3) a higher prevalence Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. The than autosomal dominant Alzheimer’s disease, and (4) a more patients/participants provided their written informed consent to homogeneous pathophysiology than those with sporadic AD. participate in this study. These characteristics place people with Down syndrome as an optimal population to be included in studies to evaluate the relationship between OSA and AD, and in clinical trials AUTHOR CONTRIBUTIONS of preventive sleep therapies for AD. Moreover, given the similarities between both sporadic and autosomal dominant SG and MM developed the study concept and design. AFa, FM, AD and AD in individuals with Down syndrome, results LV, MG, SC, AFe, MBl, MA, AA, BB, MBa, IB, and AFo acquired and therapies of these sleep studies could be beneficial for the data. SG, JP, and MM analyzed and interpreted the data, did all these groups. the statistical analysis, and drafted the manuscript. All authors This study has some limitations. Despite being one of the revised and edited the manuscript and critically revised it for largest studies on CPAP compliance, it has a relatively small important intellectual content. Frontiers in Neuroscience | www.frontiersin.org 7 March 2022 | Volume 16 | Article 838412 Giménez et al. CPAP in Adults With DS FUNDING ACKNOWLEDGMENTS This study was supported by the Spanish Respiratory Society We would like to thank the study participants and their caregivers (becas SEPAR, 2018) (738 to MM), Fondo de Investigaciones for their patience and contributions to the research. We also Sanitario (FIS), Instituto de Salud Carlos III (PI20/00836 to acknowledge Maribel Martínez for sleep nursing handling, and SG) (PI14/01126 and PI17/01019 to JF), and the CIBERNED Maria Carmona, Silvia Valldeneu, and Susana Fernández for their program (Program 1, Alzheimer’s disease), partly jointly funded help in acquiring the data reported in this manuscript. by Fondo Europeo de Desarrollo Regional, Unioìn Europea, Una manera de hacer Europa. This work was also supported by the National Institutes of Health (NIA grants 1R01AG056850- SUPPLEMENTARY MATERIAL 01A1; R21AG056974; and R01AG061566 to JF), Fundació La Marató de TV3 (20141210 to JF), and Generalitat de Catalunya The Supplementary Material for this article can be found (SLT006/17/00119 to JF). Fundació Catalana Síndrome de Down online at: https://www.frontiersin.org/articles/10.3389/fnins. and Fundació Víctor Grífols i Lucas partially supported this work. 2022.838412/full#supplementary-material REFERENCES Gottlieb, D. J., and Punjabi, N. M. (2020). Diagnosis and management of obstructive sleep apnea: a review. JAMA 323, 1389–1400. doi: 10.1001/jama. Alcolea, D., Clarimón, J., Carmona-Iragui, M., Illán-Gala, I., Morenas-Rodríguez, 2020.351 E., Barroeta, I., et al. (2019). The Sant Pau Initiative on Neurodegeneration Griffin, J. M., Meis, L., Greer, N., Jensen, A., MacDonald, R., Rutks, I., et al. 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The use, distribution or reproduction in over twenty years of data collection: a flattened curve. J. Otolaryngol. Head Neck other forums is permitted, provided the original author(s) and the copyright owner(s) Surg. 45:43. doi: 10.1186/s40463-016-0156-0 are credited and that the original publication in this journal is cited, in accordance Sawyer, A. M., Gooneratne, N. S., Marcus, C. L., Ofer, D., Richards, K. C., and with accepted academic practice. No use, distribution or reproduction is permitted Weaver, T. E. (2011). A systematic review of CPAP adherence across age groups: which does not comply with these terms. Frontiers in Neuroscience | www.frontiersin.org 9 March 2022 | Volume 16 | Article 838412