Mortality and institutionalization of patients with dementia treated in primary care: Influence of neuropsychiatric symptoms (NeDEM project)

Mortality and institutionalization of patients with dementia treated in primary care: Influence of neuropsychiatric symptoms (NeDEM project) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mortality and institutionalization of patients with dementia treated in primary care: Influence of neuropsychiatric symptoms (NeDEM project) Victoria García-Martín, M Canto de Hoyos-Alonso, Jesús Martín-Fernández, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4765073/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Sep, 2025 Read the published version in BMC Geriatrics → Version 1 posted 27 You are reading this latest preprint version Abstract Background: Neuropsychiatric symptoms (NPSs) are common in patients with dementia, but their associations with the risk of institutionalization and mortality are controversial. The objective of this study was to estimate the incidence of institutionalization and death among patients with dementia treated in primary care (PC) and to analyse the associations between NPSs and these events. Methods: This was a longitudinal analytical observational study of patients with dementia in PC with a 4-year follow-up. Data on sociodemographic, clinical and functional characteristics and prescribed treatments for dementia were collected. NPSs were examined with the Neuropsychiatric Inventory (NPI) scale and according to the presence of clinically relevant neuropsychiatric subsyndromes. The incidence of institutionalization and cumulative mortality were calculated annually and at 4 years. Survival analysis with Kaplan‒Meier curves and Cox regression was performed to analyse the influence of NPSs on institutionalization and mortality. Results: A total of 124 patients with a mean age of 82.5 (8.0) years were included, and 69.4% were women. At 4 years, the institutionalization rate in a nursing home was 29.8% (95% CI 22.0; 38.7), with a median time to institutionalization of 13.2 months (IQR: 6.8–31.5). The mortality rate was 48.4% (95% CI 39.3; 57.5), with a median survival time of 21.7 months (IQR: 14.2–32.0). The NPI score was associated with institutionalization (HR 1.27, 95% CI 1.12, 1.45) and mortality (HR 1.47, 95% CI 1.40, 1.54). Among the subsyndromes, the presence of clinically relevant apathy was associated with institutionalization (HR 2.23, 95% CI 1.29, 3.88) and mortality (HR 1.56, 95% CI 1.34, 1.81). Conclusions: In patients with dementia treated in the community for four years of follow-up, one-third of the patients were institutionalized, and half died. The intensity of the NPSs influences both institutionalization and mortality, with subsyndrome apathy (formed by the symptoms of apathy and appetite alterations) being the one that most influences both outcomes. Dementia Incidence Prognosis Mortality Institutionalization Neuropsychiatric symptoms Behavioural and psychological symptoms of dementia Apathy Neuropsychiatric Inventory Primary care. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Dementia is a health problem whose prevalence has been increasing in recent years, and it is estimated that the prevalence will continue to increase due to the progressive ageing of the population [ 1 ]. One of the most difficult problems to address in these patients is the behavioural and psychological symptoms of dementia or neuropsychiatric symptoms (NPSs). These manifestations frequently appear (50–98%) at any stage of the disease [ 2 – 7 ], and their presence worsens the disease prognosis, increasing the risk of progression to severe dementia [ 8 , 9 ], institutionalization [ 10 – 19 ] and mortality [ 8 , 11 , 20 – 22 ]. NPSs can be evaluated with different scales, among which one of the most commonly used is the Neuropsychiatric Inventory (NPI) [ 23 ]. For its study and management, its grouping into neuropsychiatric subsyndromes can also be considered [ 24 ]. The NPSs that have been most frequently associated with an increased risk of mortality are depression, anxiety, delusions, hallucinations, apathy, irritability, and agitation/aggressiveness [ 8 , 11 , 20 – 22 , 25 ]. Isolated symptoms have been associated not only with mortality but also with a higher value on the NPI scale [ 20 , 22 ], and the presence of at least one clinically significant NPS (NPI scale value ≥ 4) [ 8 , 20 , 26 ]. On the other hand, the NPSs that have been most strongly associated with institutionalization are agitation/aggressiveness, disinhibition, delusions and hallucinations [ 14 , 16 , 17 , 27 – 29 ]. The total NPI score [ 18 , 19 ], the presence of at least one NPS [ 13 , 15 ], a higher number of symptoms [ 17 ] or highly symptomatic status [ 11 ] have also been described as predictors of institutionalization. However, there are other studies in which this association between the presence of NPSs and mortality [ 29 , 30 ] or institutionalization [ 30 , 31 ] has not been reported, considering that caregiver overload is a predictor of both death [ 30 ] and patient admission to a residence [ 30 , 31 ]. Therefore, there is no uniformity in the results of studies on the impact of NPSs on institutionalization and mortality, which justifies continuing research in this field. The objective of this study was to estimate the incidence of institutionalization and death among patients with dementia treated in PC and to analyse the associations between NPSs and these events. Methods Study design, setting and participants This was a longitudinal analytical observational cohort study with a 4-year prospective follow-up in two health centres in the urban municipalities of Alcorcón and Villaviciosa de Odón (Madrid Region-Spain), which serve a population of 43,594 inhabitants. This article was prepared according to the STROBE recommendations [ 32 ]. Patients who were diagnosed with dementia and/or were receiving specific treatment (anticholinesterase and/or memantine) who had any consultation or received some care in a PC setting in 2015 and who had a known caregiver who agreed to participate in the study were included if they signed the informed consent form. Institutionalized or deceased patients were excluded on the start date of the study. Additionally, those with previous major mental disorders such as schizophrenia or other psychotic disorders and caregivers who did not understand the Spanish language were excluded. The follow-up period was from November 18, 2015, to November 17, 2019. A total of 356 patients with dementia were identified, 176 of whom met the inclusion criteria, with 129 agreeing to participate in the study. With this sample size and an expected annual mortality rate of 6% [ 33 , 34 ], the precision of our result would be 4.1%, and for an expected proportion of annual institutionalization of 16% [ 28 , 31 , 33 , 34 ], the precision would be 6.3%. Variables Baseline data Baseline sociodemographic, clinical, and functional data were collected by reviewing the patient's electronic medical record (EHR) and by interviewing the main caregiver, which included standardized questionnaires. Patient variables included age, sex and educational level; functional assessment via the Barthel index [ 35 ] with the dependency levels established by Shah et al.[ 36 ]; the developmental phase of dementia according to Reisberg's Global Deterioration Scale (GDS)[ 37 ]; specific treatment for dementia (anticholinesterase and/or memantine); and treatment for NPSs with neuroleptics and comorbidities according to the Charlson index [ 38 ]. This index includes 19 well-defined clinical situations to which a score of 1, 2, 3 or 6 points is assigned (a maximum of 33 points); it is one of the most commonly used validated indices to evaluate comorbidities[ 39 ]; has good test-retest reliability; has adequate inter- and intraobserver validity; and is significantly correlated with mortality, disability, readmission, and mean stay [ 40 ]. The index was categorized into ≤ 2 points and > 2 points to differentiate patients with no or low comorbidity (0–2 points) from those with high comorbidity (> 2 points)[ 41 ]. Data on the NPSs were collected via the validated version for the Spanish population of the Neuropsychiatric Inventory (NPI), whose total score (0-144) is calculated via the product of frequency by severity (intensity) of twelve symptoms [ 23 , 42 ]. To group the NPSs, the classification of Aalten et al. 2007 was used, which consists of four subsyndromes [ 43 ]: “hyperactivity” subsyndrome (agitation/aggression, disinhibition, irritability/lability, aberrant motor behaviour and elation/euphoria); “psychosis” subsyndrome (delusions, hallucinations, sleep behaviour); “affective” subsyndrome (depression, anxiety); and “apathy” subsyndrome (apathy/indifference and appetite/eating behaviour). For this study, clinically significant [ 2 , 44 – 46 ] or clinically relevant [ 43 , 47 , 48 ] subsyndromes were considered when at least one NPS of the subsyndrome had a value on the NPI scale ≥ 4. Finally, data on variables related to the caregiver, namely, employment status and caregiver overload, were collected by means of the short Zarit test for dementia [ 49 ], which is a shortened form of the Spanish validation of the Zarit test [ 50 , 51 ]. Follow-up data The measures of institutionalization and death outcomes were measured at 1, 2, 3 and 4 years. The data were obtained from electronic clinical records and administrative registers. Institutionalization was defined as permanent admission to a nursing home. The date of death or institutionalization was then regarded as the end of the observation period. Death and institutionalization during the follow-up period were considered "events". The events 'death', 'other dropout' or 'end of study' were censored, and the observation period was measured as days from baseline to the occurrence of the target or censoring event. Statistical analysis For descriptive statistics, means, medians or proportions were used. Chi-squared tests and Student’s t tests were used for comparisons of the baseline characteristics of the patients who were lost to follow-up versus those of patients who completed the follow-up. The cumulative annual and 4-year incidence rates of institutionalization and death were calculated. The mean and median times to death or institutionalization were calculated. Survival analysis Kaplan‒Meier survival curves were generated according to NPS intensity or according to the presence (or absence) of neuropsychiatric subsyndromes. Log-rank tests were used to test for differences between curves. Cox regression was used to calculate univariate and adjusted multivariate hazard ratios (HRs) to determine the influence of NPSs on the institutionalization and death of patients with dementia. For each event (mortality or institutionalization), two multivariate models (Cox regression) were constructed, one using the NPI value categorized using the median as the cut-off point, and the other considering the presence of clinically significant or clinically relevant subsyndromes. The models were adjusted for the remaining variables collected. The proportional hazards assumption was checked via graphical methods [ 52 ] and by studying the Schoenfeld residuals [ 53 ]. The selection of the best model was performed by assessing its alignment with the theoretical framework and the goodness of fit measured through the Akaike information criterion (AIC) and the Bayesian information criterion (BIC) [ 54 ]. Since the data originated from two different centres, standard errors were calculated by means of robust methods [ 55 ]. SPSS 26.0 (Statistical Package for Social Sciences, SPSS Inc., Chicago, IL, USA) and STATA 15 were used for the statistical analysis. Ethics approval This study was conducted following the principles of the Declaration of Helsinki and its subsequent revisions and was approved by the Clinical Research Ethics Committee of Alcorcón Foundation University Hospital on 23 September 2015 (for the initial analysis) and 02 July 2019 (for the follow-up study). Results The sociodemographic and clinical characteristics of the 129 patients who were initially included in the study, the epidemiological characteristics of the caregivers, and the data related to care-related burden have been previously described [ 7 , 56 ]. Five of the 129 patients did not have data on mortality or institutionalization at 4 years. The participants included in the analyses did not differ significantly from those excluded ( Supplement 1 ). The 124 patients included had a mean age of 82.5 (SD 8.0) years, and 69.4% were women. During the 4-year follow-up period, 37 patients were institutionalized (29.8%, 95% CI 22.0; 38.7): 12.1% in the first year, 5.5% in the second year, 7.8% in the third year, and 8.4% in the fourth year. Sixty of the 124 patients died (48.4%, 95% CI 39.3; 57.5): 8.9% in the first year, 16.8% in the second year, 20.2% in the third year, and 14.7% in the fourth year. The percentage of deaths among institutionalized patients was 45.9% (95% CI 29.5; 63.1), and among noninstitutionalized patients, it was 49.4% (95% CI 38.5; 60.4). The median follow-up was 45.1 months (IQR: 22.3–47.0), with a mean time of 35.1 (SD 14.3) months. The flow chart of the follow-up of the patients is presented in Fig. 1 . Institutionalization In the 37 institutionalized patients, the median from their inclusion in the study to their admission to residence was 13.2 months (IQR: 6.8–31.5) [mean 19.4 (14.4) months]. the Kaplan‒Meier curve for institutionalization is shown in Fig. 2 . The survival curves for institutionalization according to the total NPI value, with the median used as the cut-off point, and the presence of neuropsychiatric subsyndromes, is shown in Figs. 3 and 4. Supplement 2 shows the institutionalization survival curves according to other factors related to the patient or caregiver. In the univariate analysis, institutionalization was associated with a total NPI score > 21 points (HR 1.23, 95% CI 1.16; 1.32) and the presence of clinically relevant apathy subsyndrome (HR 2.26, 95% CI 1.31; 3.91). Other associated variables were being male (HR 1.33, 95% CI 1.02; 1.73), having a lower educational level (HR 1.52, 95% CI 1.26, 1.84) and being in treatment for dementia (HR 1.36, 95% CI 1.00; 1.84) (Table 1 ). In the multivariate analysis, in Model 1, which analyses the NPSs through subsyndromes, institutionalization was associated with the presence of clinically relevant apathy subsyndrome (HR 2.23, 95% CI 1.29; 3.88) in addition to male sex (HR 1.45, 95% CI). % 1.05; 2.00) and to a lower educational level (HR 1.33, 95% CI 1.21; 1.47). In Model 2, when the NPSs were analysed through the NPI scale, institutionalization was associated with a total NPI score > 21 points (HR 1.25, 95% CI 1.05; 1.49), and in addition to sex and educational level, institutionalization was associated with treatment for dementia (HR 1.43, 95% CI 1.10; 1.87) (Table 1 ). Table 1 Factors associated with institutionalization (univariate and multivariate Cox regression models) Univariate Multivariate Model 1 (1) Model 2 ( ² ) HR (95% CI) p HR (95% CI) p HR (95% CI) p Patient age (< 80 years) 1.11 (0.27; 4.54) 0.882 Patient sex (female) 1.33 (1.02; 1.73) 0.031 1.45 (1.05; 2.00) 0.025 1.41 (1.00; 2.00) 0.052 Patient studies (≥ secondary) 1.52 (1.26; 1.84) 0.000 1.33 (1.21; 1.47) 0.000 1.60 (1.58; 1.61) 0.000 Barthel index (independence, little or moderate dependence, > 60 points) 1.07 (0.74; 1.55) 0.715 GDS stage (GDS 3–5 mild-moderate dementia) 0.85 (0.35; 2.07) 0.719 Treatment for dementia (No) 1.36 (1.00; 1.84) 0.049 1.43 (1.10; 1.87) 0.009 Neuroleptic treatment (No) 1.17 (0.91; 1.50) 0.232 Charlson index (≤ 2 points) 0.97 (0.71; 1.33) 0.852 Caregiver's employment status (Does not work) 1.28 (0.38; 4.28) 0.688 Presence of caregiver overload (No) 1.38 (0.72; 2.65) 0.336 Apathy subsyndrome (No) (1) 2.26 (1.31; 3.91) 0.004 2.23 (1.29; 3.88) 0.004 Hyperactivity subsyndrome (No) (1) 1.51 (0.68; 3.40) 0.314 Affective subsyndrome (No) (1) 0.66 (0.27; 1.60) 0.356 Psychosis subsyndrome (No) (1) 0.86 (0.47; 1.60) 0.640 NPI Scale (≤ 21 points) 1.23 (1.16; 1.32) 0.000 1.25 (1.05; 1.49) 0.012 In bold: p statistically significant. GDS: Global Deterioration Scale (GDS 3: mild CD, borderline impairment. GDS 4: moderate CD, mild dementia. GDS 5: moderately severe CD, moderate dementia. GDS 6: severe CD, moderately severe dementia. GDS 7: very severe CD, severe dementia). 1 Cox regression model adjusted for the presence of clinically significant or relevant neuropsychiatric subsyndromes (that is, having at least some neuropsychiatric symptoms with an NPI value ≥ 4). AIC: 321.19 BIC: 324.01 2 Cox regression model adjusted for the NPI score. AIC: 325.64 BIC: 328.46 Mortality The median time to death was 21.7 months (IQR: 14.2–32.0) [mean 22.9 (SD 11.6) months], 21.8 months for the institutionalized group and 21.5 months for the noninstitutionalized group [mean 24.2 (SD 12.3) and 22.4 (DE 11.4), respectively]. Figure 5 shows the Kaplan‒Meier curves for overall mortality. The curves for mortality according to the total NPI score and the type of neuropsychiatric subsyndromes are shown in Figs. 6 and 7 . Survival and mortality curves according to other factors related to the patient are shown in Supplement 3 . In the univariate analysis, mortality was associated with a total NPI score > 21 points (HR 1.54, 95% CI 1.05; 2.26), apathy (HR 1.71, 95% CI 11.63; 1.80) and psychosis (HR 1.68, 95% CI 1.37; 2.06), which are clinically relevant. Other variables associated with mortality were older patient age (HR 2.25 CI95% 1.59; 3.20), a higher level of dependence (HR 2.95 CI95% 1.97; 4.41), greater severity of dementia (HR 2.97 CI 95% 1.18; 7.45), treatment with neuroleptics (HR 1.16 CI95% 1.05; 1.28) and a higher Charlson index score (HR 1.62 (1.39; 1.90)) (Table 2 ). In the multivariate analysis, in Model 1, which analyses the NPSs through subsyndromes, mortality was associated with the presence of clinically relevant apathy subsyndrome (HR 1.66, 95% CI 1.47; 1.87), older patient age (HR 2.22, 95% CI 1.61; 3.06), advanced stages of dementia (GDS 6–7) (HR 3.40, 95% CI 1.45; 7.98) and more than two comorbidities according to the Charlson index (HR 1.67, 95% CI 1.29; 2.17). In Model 2, which analyses the NPSs through the NPI scale, mortality was associated with a total NPI score > 21 points (HR 1.47, 95% CI 1.38; 1.58) and older patient age (HR 2.08, 95% CI 1.62; 2.69), higher GDS (greater severity) (HR 3.38, 95% CI 1.34; 8.52) and Charlson index > 2 points (HR 1.78, 95% CI 1.40; 2.26) (Table 2 ). Table 2 Factors associated with mortality (univariate and multivariate Cox regression models) Univariate Multivariate Model 1 (1) Model 2 ( ² ) HR (95% CI) p HR (95% CI) p HR (95% CI) p Patient age (< 80 years) 2.25 (1.59; 3.20) 0.000 2.22 (1.61; 3.06) 0.000 2.08 (1.62; 2.69) 0.000 Patient sex (female) 1.18 (0.76; 1.85) 0.462 Patient studies (≥ secondary) 1.18 (0.99; 1.40) 0.072 Barthel index (independence, little or moderate dependence, > 60 points) 2.95 (1.97; 4.41) 0.000 GDS stage (GDS 3–5 mild-moderate dementia) 2.97 (1.18; 7.45) 0.020 3.40 (1.45; 7.98) 0.005 3.38 (1.34; 8.52) 0.010 Treatment for dementia (No) 0.63 (0.38; 1.05) 0.078 Neuroleptic treatment (No) 1.16 (1.05; 1.28) 0.003 Charlson index (≤ 2 points) 1.62 (1.39; 1.90) 0.000 1.67 (1.29; 2.17) 0.000 1.78 (1.40; 2.26) 0.000 Apathy subsyndrome (No) (1) 1.71 (1.63; 1.80) 0.000 1.66 (1.47; 1.87) 0.000 Hyperactivity subsyndrome (No) (1) 0.82 (0.35; 1.89) 0.638 Affective subsyndrome (No) (1) 1.30 (0.96; 1.75) 0.091 Psychosis subsyndrome (No) (1) 1.68 (1.37; 2.06) 0.000 NPI Scale (≤ 21 points) 1.54 (1.05; 2.26) 0.026 1.47 (1.38; 1.58) 0.000 In bold: p statistically significant. GDS: Global Deterioration Scale (GDS 3: mild CD, borderline impairment. GDS 4: moderate CD, mild dementia. GDS 5: moderately severe CD, moderate dementia. GDS 6: severe CD, moderately severe dementia. GDS 7: very severe CD, severe dementia). 1 Cox regression model adjusted for the presence of neuropsychiatric subsyndromes clinically significant or relevant (that is, they have at least some neuropsychiatric symptoms with an NPI value ≥ 4) AIC: 512.35 BIC: 515.17 2 Cox regression model adjusted for total NPI score AIC: 513.88 BIC: 516.70 Discussion In patients with dementia treated with PC, the NPSs influence institutionalization and mortality, with subsyndrome apathy (formed by symptoms of apathy and appetite alterations) being the most associated with both. In the 4 years of follow-up, one-third of the patients were institutionalized. The average duration from the start of the study until they entered a residence hall was 13 months. The annual incidence of institutionalization was 5.5 to 12 institutionalized per 100 person-years, which was higher in the first year than in the rest of the study period. Other studies carried out in specialized memory clinics in France and the Netherlands have reported a higher annual incidence of institutionalization, ranging from 11.8–23.5% [ 28 , 31 , 33 , 34 ]. These differences may be related to sociocultural and economic factors that influence the decision to enter a family member in a residence, as well as the severity of dementia, since the published incidence is higher when the population has moderate–severe dementia [ 31 ] than when other studies include only mild–moderate dementia [ 33 , 34 ]. Half of the patients died during the 4-year follow-up. The mean duration from the start of the study to death was 22 months. The annual incidence of mortality that we found in our study was 8.9 to 20.2 deaths/100 person-years, which was higher than that reported in other studies, which reported incidences ranging from 5.9–7.4% [ 33 , 34 ]. The higher mortality in our study can be attributed to the greater severity of dementia, since these studies included only patients with mild–moderate dementia and lowest average NPI score. Factors associated with institutionalization In our study, institutionalization was associated with the total NPI score and the presence of apathy subsyndrome when the symptoms are very intense. In other studies, highly symptomatic NPSs have also been described as predictors of patient institutionalization [ 11 ] In addition, high values on the NPI scale or a greater number of symptoms in patients have been reported [ 11 , 17 – 19 ]. The presence of apathy in patients with dementia has also been associated with a higher risk of admission to a residence, regardless of the burden of the caregiver [ 57 ], and this is especially notable for patients with early-onset dementia [ 58 ] and those with Lewy body dementia [ 59 ]. On the other hand, altered appetite, which is part of the apathy subsyndrome, has been described as a predictor of institutionalization along with other NPSs, although in only a few studies [ 14 ]. However, we did not find a relationship between institutionalization and other NPSs or subsyndromes, in contrast to other studies in which an associations with agitation/aggressiveness [ 14 , 16 , 17 ], disinhibition [ 14 , 27 ], symptoms within the hyperactivity subsyndrome, and delusions and hallucinations, which are part of the psychosis subsyndrome [ 14 , 16 , 17 , 29 ], and anxiety and depression (affective subsyndrome) were reported [ 16 , 17 ]. On the other hand, we found that being male with a lower level of education and being in treatment for dementia were associated with institutionalization. A systematic review on the predictors of admission to residences in older people revealed that the results for both male sex and a low level of education or low income were inconsistent, with the strongest predictors being age, dementia or functional impairment [ 60 ]. In a study carried out in Spain with people in a situation of dependency, the risk of institutionalization was three times higher among men than among women [ 61 ]. However, in studies carried out in patients with dementia, there were no consistent results, since some studies have shown that the risk of institutionalization was greater among women [ 62 , 63 ], whereas others showed this to be true among males [ 64 , 65 ]. With respect to the level in the studies, other authors have reported more institutionalization of patients with a higher level of education [ 27 , 66 ]. These differences from the work we present may be due to the sociocultural context. In our population, although we could not collect data on the socioeconomic level of the patients, we consider that the level of the studies can be interpreted as a "proxy" of the economic level. A lower educational level would imply having fewer economic resources, which would limit the possibility of hiring external help to maintain care at home and could force institutionalization when the level of dependency increases and more time of care is needed. In this sense, in our case, the low level of education of the patients was associated caregiver overload in a previous work [ 56 ]. Managing behavioural symptoms can be difficult, and caregivers are sometimes unable to control the situation, which can lead to the institutionalization of patients [ 67 ]. The presence of caregiver overload has been described in multiple studies as a predictor of institutionalization [ 13 , 15 , 17 , 27 , 30 , 31 , 66 , 68 , 69 ]; however, we have not been able to demonstrate such an association. In other studies, symptomatic treatments for NPSs, such as neuroleptics, have been shown to increase the risk of institutionalization [ 18 ], although in our case, we were not able to verify this association. In our study, we found that the specific treatment for dementia (anticholinesterase drugs and memantine) is related to admission to the hospital. Some anticholinesterase drugs (rivastigmine) are used to mitigate NPSs in patients with types of dementia in which neuroleptics are contraindicated, such as Lewy body dementia. The lack of control of the NPSs in these patients could cause institutionalization of the patient, which could be attributed to anticholinesterase drugs when, in reality, the theoretical cause could be the underlying NPS. Another possible explanation for the association between this drug group and institutionalization is the cholinergic side effects that these drugs cause, with interactions with other drugs that are used by these patients (for example, drugs for urinary incontinence), worsening the symptoms of cognitive deterioration. The findings in other studies are variable. One of them reported that patients who had received treatment before or within the year of diagnosis had a higher risk of admission to residences than did those without treatment; their interpretation was that patients without treatment were in earlier stages of the disease [ 63 ], which could explain the association between anticholinesterase or memantine treatment and admission. However, other authors reported either that patients who were undergoing treatment had a lower risk of institutionalization [ 70 , 71 ] or that there was no association between the two [ 72 ]. Factors associated with mortality Regarding the relationship between NPSs and mortality, the results revealed that a higher score on the NPI scale, which analyses the intensity of NPSs, is associated with mortality, which is consistent with the findings of other studies [ 20 , 22 ]. Among the different NPSs, only the presence of apathy syndrome was associated with mortality in our study. Apathy has been described as a predictor of mortality, as well as an isolated symptom [ 20 , 73 , 74 ], as when it is part of the apathy subsyndrome (apathy and/or appetite disturbances) [ 11 , 22 ]. Some authors suggest that this may be explained by the fact that apathy leads to a more serious clinical profile in Alzheimer's dementia patients, with worse functional progression and a higher risk of mortality [ 75 ]. A listless neurobehavioral profile also predicts death in patients with frontotemporal degeneration [ 76 ]. In our study, we also found an association between mortality and the presence of psychotic symptoms (delusions and/or hallucinations), as in other studies [ 8 , 20 , 21 ], although this association could not be confirmed in the multivariate analysis. An association with agitation has been reported [ 8 , 20 , 21 , 25 ], and one study reported no relationship between subsyndromes and mortality [ 29 ]. Neuroleptic treatment in patients with dementia has been associated with mortality in several studies [ 20 , 77 – 80 ]. In our case, we found an association only in the univariate analysis, as was the case with psychotic symptoms, which are usually treated with these drugs. Notably, the use of neuroleptics, especially those used for agitation and psychotic symptoms, was shown to be associated with a higher risk of cardiovascular events [ 81 ] and a higher risk of apathy [ 75 ], both of which can increase mortality. With respect to other sociodemographic and clinical characteristics, mortality increased in older, more dependent patients and those with more severe dementia, which has been described in the literature as being associated with age [ 8 , 20 , 21 , 79 , 82 , 83 ] and with disease severity [ 21 , 79 , 82 ]. In our study, having more than two comorbidities measured with the Charlson index was associated with mortality. In people with dementia, comorbidities are frequent, cause an increase in disability, reduce the quality of life of the patient and the caregiver [ 84 ] and increase the risk of mortality [ 20 , 83 , 85 ]. There is no unanimity on how to analyse comorbidities in mortality studies. Although the Charlson index is one of the most widely used indices in the assessment of comorbidities [ 39 ], it does not include situations closely related to institutionalization or death among elderly individuals, such as hip fracture. Limitations and strengths Although limited by geographical area, which may limit its external validity, the population included in our study has allowed us to carry out a prospective study of representative sample of patients with dementia in our region who live and are cared for in the community. Neuropsychiatric symptoms can be analysed as isolated symptoms, as a group of symptoms or subsyndromes, with the global measure of the NPI scale, among other methods, which makes it difficult to compare studies. In this work, we have chosen some of the measures that best represent the NPSs, that is, the presence or absence of symptoms grouped into subsyndromes and the global values of the NPI scale in which the intensities of twelve NPSs are measured. This study has allowed us to provide evidence on the role that NPSs play in the institutionalization and survival of patients with dementia, with a method that allows us to provide better evidence on this problem and overcome some methodological limitations of some studies of dementia with which we can compare our results by proposing a prospective design with a 4-year follow-up. Clinical and research applications From the perspective of PC, it is necessary to continue investigating the impact of NPSs on institutionalization and mortality, as well as on the quality of life of patients and caregivers by designing studies with larger sample sizes that consider sociocultural factors and monitor the possible biases that may occur in such a complex field due to the multiple interactions of different clinical and sociofamily circumstances. Neurobehavioral characteristics could be useful for predicting survival [ 76 ]. The study of apathy may be of special interest, with the development of more effective and user-friendly measurement tools in clinical practice that allow its early detection [ 76 ] and differentiate it from depression to avoid unnecessary treatments. Although apathy has a neuropathological basis [ 76 ], it can be associated with treatments such as neuroleptics [ 75 ]. These drugs are indicated in the management of other NPSs, such as delusions or agitation, when their intensity entails severe anguish to the patient and/or danger to the caregivers or the patients themselves, while reassessing their need from time to time [ 67 , 86 – 88 ]. Antidepressants have also been associated with worsening apathy over time [ 89 ]. Investigating the periods of use of neuroleptics and other psychoactive drugs used to treat NPSs and observing their impact on the progression of the NPSs treated, on the appearance of new NPSs or on the triggering of therapeutic cascades may be helpful toward developing management strategies. We must also continue addressing the question regarding the most appropriate way to measure comorbidity in patients with dementia, evaluating possible groupings of diseases and/or drugs, which allows the design of indices or global measures that can be incorporated into the analyses to better explain the relationships between NPSs and institutionalization or mortality. Conclusions The institutionalization and mortality of patients with dementia treated in primary care are associated with the intensity of neuropsychiatric symptoms measured with the NPI scale and with the presence of apathy. Neuroleptics were associated with mortality, and anticholinesterase drugs and/or memantine were associated with institutionalization. Mortality was also associated with older age, severity of dementia, and greater comorbidity, whereas being male with a low educational level was a risk factor for institutionalization. Given the importance of apathy for both institutionalization and mortality, it seems appropriate to investigate adequate methods of early detection and management of this symptom that can improve the prognosis of patients and help caregivers. In the same way, it is important to see the role that the treatments used in dementia can have in the appearance and/or worsening of apathy, in the worsening of cognitive deterioration and in the secondary use of other drugs by causing therapeutic cascades. It is also advisable to implement training measures, for both health workers and caregivers, to help detect NPSs, provide guidance on their prevention and management, and avoid the initiation and/or prolongation of drug treatments when they are not necessary. Abbreviations NPS neuropsychiatric symptoms PC primary care NPI Neuropsychiatric Inventory STROBE Strengthening the Reporting of OBservational studies in Epidemiology EHR Electronic health record GDS Global deterioration scale CD Cognitive decline Declarations Ethics approval and consent to participate This study was carried out following the principles of the Declaration of Helsinki and its subsequent revisions and was approved by the Clinical Research Ethics Committee of the Alcorcón Foundation University Hospital on September 23, 2015 (for baseline analysis) and July 2, 2019 (for the follow-up study). Informed consent was requested from the caregivers responsible for the patients who were interviewed and, in the case of professional caregivers, from the legal representative of the patient. All caregivers were educated enough to read and understand the informed consent form. At the discretion of the responsible physician, consent was also requested from patients who were considered capable of providing it. Consent for publication Not applicable. Availability of data and materials The datasets used and analysed during the current study are available from the corresponding author ( [email protected] ) upon reasonable request. All the data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests The authors declare that they have no competing interests. Funding This study received a grant for manuscript translation and publication from the Foundation for Research and Biomedical Innovation in Primary Care (FIIBAP) 2024. Authors' contributions VG, MCH and IDC conceived the study. VG, MCH, JM and IDC contributed to the design. VG and MCH were responsible for the data collection. VG, MCH, JM and IDC analysed and interpreted the data. VG and MCH wrote the first draft of the manuscript. JM and IDC revised the manuscript and provided substantive contributions. All the authors read and approved the final manuscript. Acknowledgements We thank the patients and caregivers who agreed to participate in the study and the researchers Rosalía Delgado Puebla, Paula García Domingo, Erika Hernández Melo and Javier López de Haro de Torres who participated in the initial data collection. Authors' information (optional) Victoria García-Martín (ORCID: https://orcid.org/0000-0002-1560-9842) PhD student in Epidemiology and Public Health at Universidad Rey Juan Carlos (Rey Juan Carlos University), Madrid, Spain. Preventive Medicine and Public Health Service, Infanta Leonor-Virgen de la Torre University Hospital, Madrid, Spain. M Canto de Hoyos-Alonso (ORCID:https://orcid.org/0000-0002-1409-893X) Pedro Laín Entralgo Health Care Center, Alcorcón, Primary Care Management, Madrid Health Service, Madrid, Spain. Network for Research on Chronicity, Primary Care and Health Promotion (RICAPPS), Spain Jesus Martin Fernandez (ORCID: https://orcid.org/0000-0001-9545-1549) Network for Research on Chronicity, Primary Care and Health Promotion (RICAPPS), Spain. Family and Community Medicine Teaching Unit Oeste, Primary Care Management, Madrid Health Service, Móstoles, Madrid, Spain. Department of Medical Specialties and Public Health, Universidad Rey Juan Carlos (Rey Juan Carlos University), Alcorcón, Madrid, Spain Gregorio Marañón Health Research Institute IiSGM Isabel del Cura-González (ORCID IdCG: 00002-3931-5304) Network for Research on Chronicity, Primary Care and Health Promotion (RICAPPS), Spain. Department of Medical Specialties and Public Health, Universidad Rey Juan Carlos (Rey Juan Carlos University), Alcorcón, Madrid, Spain Research Unit, Primary Care Management, Madrid Health Service, Madrid, Spain. Ageing Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden. 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Service","correspondingAuthor":false,"prefix":"","firstName":"M","middleName":"Canto","lastName":"de Hoyos-Alonso","suffix":""},{"id":344068697,"identity":"0fac4b77-15ad-4b97-a5a0-e0321bf70878","order_by":2,"name":"Jesús Martín-Fernández","email":"","orcid":"","institution":"Family and Community Medicine Teaching Unit Oeste, Primary Care Management, Madrid Health Service, Móstoles","correspondingAuthor":false,"prefix":"","firstName":"Jesús","middleName":"","lastName":"Martín-Fernández","suffix":""},{"id":344068698,"identity":"edf7a70a-772e-480e-996e-efa171ee722a","order_by":3,"name":"Isabel del Cura-González","email":"","orcid":"","institution":"Research Unit, Primary Care Management, Madrid Health Service","correspondingAuthor":false,"prefix":"","firstName":"Isabel","middleName":"del","lastName":"Cura-González","suffix":""}],"badges":[],"createdAt":"2024-07-18 21:23:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4765073/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4765073/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12877-025-06339-0","type":"published","date":"2025-09-24T15:58:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64568259,"identity":"89d22370-b89f-49c9-89d4-a73b56c8c5c0","added_by":"auto","created_at":"2024-09-16 00:38:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90413,"visible":true,"origin":"","legend":"\u003cp\u003ePatient follow-up flow chart (flow chart)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/09aa5701d65969b7b220530e.png"},{"id":64569251,"identity":"1010ed5e-a436-4b8f-80e1-fa7ccb76a4af","added_by":"auto","created_at":"2024-09-16 00:46:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14065,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve for institutionalization\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/45c1db02a7d308178fa8e43b.png"},{"id":64569249,"identity":"1147b45f-a297-420e-915c-7f40c552afd3","added_by":"auto","created_at":"2024-09-16 00:46:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":18890,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve for institutionalization according to the total NPI score\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/cf3477eec939b604f7f291ff.png"},{"id":64568263,"identity":"23cfb6d6-1fb7-49e7-90c1-248990545e9b","added_by":"auto","created_at":"2024-09-16 00:38:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44584,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve for institutionalization according to the presence of clinically relevant neuropsychiatric subsyndromes\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/700ec40f03fbdff184ecdf55.png"},{"id":64569253,"identity":"dc260963-bfd8-4b3d-b675-aa92ab2f2b84","added_by":"auto","created_at":"2024-09-16 00:46:58","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":13360,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves for overall mortality\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/abc9e6f12406b8a89e91729d.png"},{"id":64569837,"identity":"d9f4c16b-5f7b-4c81-9441-a9321a5e4186","added_by":"auto","created_at":"2024-09-16 00:54:58","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":17244,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curve for mortality according to the total NPI score\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/f643c9e557ad455641470cd4.png"},{"id":64568266,"identity":"7777d22c-16af-4b1b-969a-bb213ae21cfb","added_by":"auto","created_at":"2024-09-16 00:38:58","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":43872,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves for mortality according to the presence of clinically relevant neuropsychiatric subsyndromes\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/5c7573e26f09c29c52c71e5a.png"},{"id":92430594,"identity":"d0e933af-c1a6-4e03-b03d-e8a9f285d30d","added_by":"auto","created_at":"2025-09-29 16:06:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1277925,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/48a23a2e-5ccb-4423-be60-77dbe3943fb3.pdf"},{"id":64568260,"identity":"6d3754aa-2cb1-40c5-94aa-383f07fb1db9","added_by":"auto","created_at":"2024-09-16 00:38:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46200,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/0c3634af03e74535fa98225e.docx"},{"id":64569250,"identity":"1b1e0b7b-5bb5-4c3f-b23f-7c55f820e14b","added_by":"auto","created_at":"2024-09-16 00:46:58","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":187795,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/b85ecf6f55c310def917ccec.docx"},{"id":64568261,"identity":"4a87fd3c-2cf3-4293-908b-a4f409c20831","added_by":"auto","created_at":"2024-09-16 00:38:58","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":159490,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4765073/v1/88038051599a611adbea5513.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mortality and institutionalization of patients with dementia treated in primary care: Influence of neuropsychiatric symptoms (NeDEM project)","fulltext":[{"header":"Background","content":"\u003cp\u003eDementia is a health problem whose prevalence has been increasing in recent years, and it is estimated that the prevalence will continue to increase due to the progressive ageing of the population [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne of the most difficult problems to address in these patients is the behavioural and psychological symptoms of dementia or neuropsychiatric symptoms (NPSs). These manifestations frequently appear (50\u0026ndash;98%) at any stage of the disease [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and their presence worsens the disease prognosis, increasing the risk of progression to severe dementia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], institutionalization [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and mortality [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. NPSs can be evaluated with different scales, among which one of the most commonly used is the Neuropsychiatric Inventory (NPI) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For its study and management, its grouping into neuropsychiatric subsyndromes can also be considered [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe NPSs that have been most frequently associated with an increased risk of mortality are depression, anxiety, delusions, hallucinations, apathy, irritability, and agitation/aggressiveness [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Isolated symptoms have been associated not only with mortality but also with a higher value on the NPI scale [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and the presence of at least one clinically significant NPS (NPI scale value\u0026thinsp;\u0026ge;\u0026thinsp;4) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the other hand, the NPSs that have been most strongly associated with institutionalization are agitation/aggressiveness, disinhibition, delusions and hallucinations [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The total NPI score [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], the presence of at least one NPS [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], a higher number of symptoms [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] or highly symptomatic status [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] have also been described as predictors of institutionalization. However, there are other studies in which this association between the presence of NPSs and mortality [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] or institutionalization [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] has not been reported, considering that caregiver overload is a predictor of both death [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and patient admission to a residence [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, there is no uniformity in the results of studies on the impact of NPSs on institutionalization and mortality, which justifies continuing research in this field.\u003c/p\u003e \u003cp\u003eThe objective of this study was to estimate the incidence of institutionalization and death among patients with dementia treated in PC and to analyse the associations between NPSs and these events.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design, setting and participants\u003c/h2\u003e \u003cp\u003eThis was a longitudinal analytical observational cohort study with a 4-year prospective follow-up in two health centres in the urban municipalities of Alcorc\u0026oacute;n and Villaviciosa de Od\u0026oacute;n (Madrid Region-Spain), which serve a population of 43,594 inhabitants. This article was prepared according to the STROBE recommendations [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients who were diagnosed with dementia and/or were receiving specific treatment (anticholinesterase and/or memantine) who had any consultation or received some care in a PC setting in 2015 and who had a known caregiver who agreed to participate in the study were included if they signed the informed consent form. Institutionalized or deceased patients were excluded on the start date of the study. Additionally, those with previous major mental disorders such as schizophrenia or other psychotic disorders and caregivers who did not understand the Spanish language were excluded. The follow-up period was from November 18, 2015, to November 17, 2019.\u003c/p\u003e \u003cp\u003eA total of 356 patients with dementia were identified, 176 of whom met the inclusion criteria, with 129 agreeing to participate in the study. With this sample size and an expected annual mortality rate of 6% [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], the precision of our result would be 4.1%, and for an expected proportion of annual institutionalization of 16% [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], the precision would be 6.3%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eVariables\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eBaseline data\u003c/h2\u003e \u003cp\u003eBaseline sociodemographic, clinical, and functional data were collected by reviewing the patient's electronic medical record (EHR) and by interviewing the main caregiver, which included standardized questionnaires. Patient variables included age, sex and educational level; functional assessment via the Barthel index [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] with the dependency levels established by Shah et al.[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; the developmental phase of dementia according to Reisberg's Global Deterioration Scale (GDS)[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]; specific treatment for dementia (anticholinesterase and/or memantine); and treatment for NPSs with neuroleptics and comorbidities according to the Charlson index [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This index includes 19 well-defined clinical situations to which a score of 1, 2, 3 or 6 points is assigned (a maximum of 33 points); it is one of the most commonly used validated indices to evaluate comorbidities[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]; has good test-retest reliability; has adequate inter- and intraobserver validity; and is significantly correlated with mortality, disability, readmission, and mean stay [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The index was categorized into \u0026le;\u0026thinsp;2 points and \u0026gt;\u0026thinsp;2 points to differentiate patients with no or low comorbidity (0\u0026ndash;2 points) from those with high comorbidity (\u0026gt;\u0026thinsp;2 points)[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eData on the NPSs were collected via the validated version for the Spanish population of the Neuropsychiatric Inventory (NPI), whose total score (0-144) is calculated via the product of frequency by severity (intensity) of twelve symptoms [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. To group the NPSs, the classification of Aalten et al. 2007 was used, which consists of four subsyndromes [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]: \u0026ldquo;hyperactivity\u0026rdquo; subsyndrome (agitation/aggression, disinhibition, irritability/lability, aberrant motor behaviour and elation/euphoria); \u0026ldquo;psychosis\u0026rdquo; subsyndrome (delusions, hallucinations, sleep behaviour); \u0026ldquo;affective\u0026rdquo; subsyndrome (depression, anxiety); and \u0026ldquo;apathy\u0026rdquo; subsyndrome (apathy/indifference and appetite/eating behaviour). For this study, clinically significant [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] or clinically relevant [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] subsyndromes were considered when at least one NPS of the subsyndrome had a value on the NPI scale\u0026thinsp;\u0026ge;\u0026thinsp;4.\u003c/p\u003e \u003cp\u003eFinally, data on variables related to the caregiver, namely, employment status and caregiver overload, were collected by means of the short Zarit test for dementia [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], which is a shortened form of the Spanish validation of the Zarit test [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up data\u003c/h2\u003e \u003cp\u003eThe measures of institutionalization and death outcomes were measured at 1, 2, 3 and 4 years. The data were obtained from electronic clinical records and administrative registers. Institutionalization was defined as permanent admission to a nursing home. The date of death or institutionalization was then regarded as the end of the observation period. Death and institutionalization during the follow-up period were considered \"events\". The events 'death', 'other dropout' or 'end of study' were censored, and the observation period was measured as days from baseline to the occurrence of the target or censoring event.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor descriptive statistics, means, medians or proportions were used. Chi-squared tests and Student\u0026rsquo;s t tests were used for comparisons of the baseline characteristics of the patients who were lost to follow-up versus those of patients who completed the follow-up. The cumulative annual and 4-year incidence rates of institutionalization and death were calculated. The mean and median times to death or institutionalization were calculated.\u003c/p\u003e \u003cp\u003eSurvival analysis\u003c/p\u003e \u003cp\u003eKaplan‒Meier survival curves were generated according to NPS intensity or according to the presence (or absence) of neuropsychiatric subsyndromes. Log-rank tests were used to test for differences between curves. Cox regression was used to calculate univariate and adjusted multivariate hazard ratios (HRs) to determine the influence of NPSs on the institutionalization and death of patients with dementia. For each event (mortality or institutionalization), two multivariate models (Cox regression) were constructed, one using the NPI value categorized using the median as the cut-off point, and the other considering the presence of clinically significant or clinically relevant subsyndromes. The models were adjusted for the remaining variables collected.\u003c/p\u003e \u003cp\u003eThe proportional hazards assumption was checked via graphical methods [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] and by studying the Schoenfeld residuals [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. The selection of the best model was performed by assessing its alignment with the theoretical framework and the goodness of fit measured through the Akaike information criterion (AIC) and the Bayesian information criterion (BIC) [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Since the data originated from two different centres, standard errors were calculated by means of robust methods [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSPSS 26.0 (Statistical Package for Social Sciences, SPSS Inc., Chicago, IL, USA) and STATA 15 were used for the statistical analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003e This study was conducted following the principles of the Declaration of Helsinki and its subsequent revisions and was approved by the Clinical Research Ethics Committee of Alcorc\u0026oacute;n Foundation University Hospital on 23 September 2015 (for the initial analysis) and 02 July 2019 (for the follow-up study).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe sociodemographic and clinical characteristics of the 129 patients who were initially included in the study, the epidemiological characteristics of the caregivers, and the data related to care-related burden have been previously described [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Five of the 129 patients did not have data on mortality or institutionalization at 4 years. The participants included in the analyses did not differ significantly from those excluded (\u003cb\u003eSupplement 1\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eThe 124 patients included had a mean age of 82.5 (SD 8.0) years, and 69.4% were women.\u003c/p\u003e \u003cp\u003eDuring the 4-year follow-up period, 37 patients were institutionalized (29.8%, 95% CI 22.0; 38.7): 12.1% in the first year, 5.5% in the second year, 7.8% in the third year, and 8.4% in the fourth year. Sixty of the 124 patients died (48.4%, 95% CI 39.3; 57.5): 8.9% in the first year, 16.8% in the second year, 20.2% in the third year, and 14.7% in the fourth year. The percentage of deaths among institutionalized patients was 45.9% (95% CI 29.5; 63.1), and among noninstitutionalized patients, it was 49.4% (95% CI 38.5; 60.4).\u003c/p\u003e \u003cp\u003eThe median follow-up was 45.1 months (IQR: 22.3\u0026ndash;47.0), with a mean time of 35.1 (SD 14.3) months. The flow chart of the follow-up of the patients is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eInstitutionalization\u003c/h3\u003e\n\u003cp\u003eIn the 37 institutionalized patients, the median from their inclusion in the study to their admission to residence was 13.2 months (IQR: 6.8\u0026ndash;31.5) [mean 19.4 (14.4) months]. the Kaplan‒Meier curve for institutionalization is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe survival curves for institutionalization according to the total NPI value, with the median used as the cut-off point, and the presence of neuropsychiatric subsyndromes, is shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and 4.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSupplement 2\u003c/b\u003e shows the institutionalization survival curves according to other factors related to the patient or caregiver.\u003c/p\u003e \u003cp\u003eIn the univariate analysis, institutionalization was associated with a total NPI score\u0026thinsp;\u0026gt;\u0026thinsp;21 points (HR 1.23, 95% CI 1.16; 1.32) and the presence of clinically relevant apathy subsyndrome (HR 2.26, 95% CI 1.31; 3.91). Other associated variables were being male (HR 1.33, 95% CI 1.02; 1.73), having a lower educational level (HR 1.52, 95% CI 1.26, 1.84) and being in treatment for dementia (HR 1.36, 95% CI 1.00; 1.84) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the multivariate analysis, in Model 1, which analyses the NPSs through subsyndromes, institutionalization was associated with the presence of clinically relevant apathy subsyndrome (HR 2.23, 95% CI 1.29; 3.88) in addition to male sex (HR 1.45, 95% CI). % 1.05; 2.00) and to a lower educational level (HR 1.33, 95% CI 1.21; 1.47). In Model 2, when the NPSs were analysed through the NPI scale, institutionalization was associated with a total NPI score\u0026thinsp;\u0026gt;\u0026thinsp;21 points (HR 1.25, 95% CI 1.05; 1.49), and in addition to sex and educational level, institutionalization was associated with treatment for dementia (HR 1.43, 95% CI 1.10; 1.87) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFactors associated with institutionalization (univariate and multivariate Cox regression models)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c10\" namest=\"c5\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eModel 1\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eModel 2\u003csup\u003e(\u003c/sup\u003e\u0026sup2;\u003csup\u003e)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient age (\u0026lt;\u0026thinsp;80 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.27; 4.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.882\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient sex (female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.02; 1.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.031\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(1.05; 2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.00; 2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.052\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient studies (\u0026ge;\u0026thinsp;secondary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.26; 1.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(1.21; 1.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.58; 1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBarthel index (independence, little or moderate dependence, \u0026gt; 60 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.74; 1.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.715\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDS stage (GDS 3\u0026ndash;5 mild-moderate dementia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.35; 2.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.719\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment for dementia (No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.00; 1.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.049\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.10; 1.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuroleptic treatment (No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.91; 1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson index (\u0026le;\u0026thinsp;2 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.71; 1.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.852\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaregiver's employment status (Does not work)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.38; 4.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of caregiver overload (No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.72; 2.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.336\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApathy subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.31; 3.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(1.29; 3.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperactivity subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.68; 3.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.314\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAffective subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.27; 1.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsychosis subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.47; 1.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPI Scale (\u0026le;\u0026thinsp;21 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.16; 1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.05; 1.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eIn bold: p statistically significant. GDS: Global Deterioration Scale (GDS 3: mild CD, borderline impairment. GDS 4: moderate CD, mild dementia. GDS 5: moderately severe CD, moderate dementia. GDS 6: severe CD, moderately severe dementia. GDS 7: very severe CD, severe dementia).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Cox regression model adjusted for the presence of clinically significant or relevant neuropsychiatric subsyndromes (that is, having at least some neuropsychiatric symptoms with an NPI value\u0026thinsp;\u0026ge;\u0026thinsp;4).\u003c/p\u003e \u003cp\u003eAIC: 321.19\u003c/p\u003e \u003cp\u003eBIC: 324.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e2\u003c/sup\u003e Cox regression model adjusted for the NPI score.\u003c/p\u003e \u003cp\u003eAIC: 325.64\u003c/p\u003e \u003cp\u003eBIC: 328.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMortality\u003c/h2\u003e \u003cp\u003eThe median time to death was 21.7 months (IQR: 14.2\u0026ndash;32.0) [mean 22.9 (SD 11.6) months], 21.8 months for the institutionalized group and 21.5 months for the noninstitutionalized group [mean 24.2 (SD 12.3) and 22.4 (DE 11.4), respectively]. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows the Kaplan‒Meier curves for overall mortality.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe curves for mortality according to the total NPI score and the type of neuropsychiatric subsyndromes are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSurvival and mortality curves according to other factors related to the patient are shown in \u003cb\u003eSupplement 3\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eIn the univariate analysis, mortality was associated with a total NPI score\u0026thinsp;\u0026gt;\u0026thinsp;21 points (HR 1.54, 95% CI 1.05; 2.26), apathy (HR 1.71, 95% CI 11.63; 1.80) and psychosis (HR 1.68, 95% CI 1.37; 2.06), which are clinically relevant. Other variables associated with mortality were older patient age (HR 2.25 CI95% 1.59; 3.20), a higher level of dependence (HR 2.95 CI95% 1.97; 4.41), greater severity of dementia (HR 2.97 CI 95% 1.18; 7.45), treatment with neuroleptics (HR 1.16 CI95% 1.05; 1.28) and a higher Charlson index score (HR 1.62 (1.39; 1.90)) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the multivariate analysis, in Model 1, which analyses the NPSs through subsyndromes, mortality was associated with the presence of clinically relevant apathy subsyndrome (HR 1.66, 95% CI 1.47; 1.87), older patient age (HR 2.22, 95% CI 1.61; 3.06), advanced stages of dementia (GDS 6\u0026ndash;7) (HR 3.40, 95% CI 1.45; 7.98) and more than two comorbidities according to the Charlson index (HR 1.67, 95% CI 1.29; 2.17). In Model 2, which analyses the NPSs through the NPI scale, mortality was associated with a total NPI score\u0026thinsp;\u0026gt;\u0026thinsp;21 points (HR 1.47, 95% CI 1.38; 1.58) and older patient age (HR 2.08, 95% CI 1.62; 2.69), higher GDS (greater severity) (HR 3.38, 95% CI 1.34; 8.52) and Charlson index\u0026thinsp;\u0026gt;\u0026thinsp;2 points (HR 1.78, 95% CI 1.40; 2.26) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFactors associated with mortality (univariate and multivariate Cox regression models)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c13\" namest=\"c7\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eModel 1\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e \u003cp\u003eModel 2\u003csup\u003e(\u003c/sup\u003e\u0026sup2;\u003csup\u003e)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient age (\u0026lt;\u0026thinsp;80 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.59; 3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e2.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.61; 3.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1.62; 2.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient sex (female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(0.76; 1.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.462\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient studies (\u0026ge;\u0026thinsp;secondary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(0.99; 1.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBarthel index (independence, little or moderate dependence, \u0026gt; 60 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.97; 4.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDS stage (GDS 3\u0026ndash;5 mild-moderate dementia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.18; 7.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.45; 7.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1.34; 8.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.010\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment for dementia (No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(0.38; 1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuroleptic treatment (No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.05; 1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson index (\u0026le;\u0026thinsp;2 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.39; 1.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.29; 2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1.40; 2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApathy subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.63; 1.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(1.47; 1.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperactivity subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(0.35; 1.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAffective subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(0.96; 1.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsychosis subsyndrome (No)\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.37; 2.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPI Scale (\u0026le;\u0026thinsp;21 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e(1.05; 2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1.38; 1.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"13\" nameend=\"c13\" namest=\"c1\"\u003e \u003cp\u003eIn bold: p statistically significant. GDS: Global Deterioration Scale (GDS 3: mild CD, borderline impairment. GDS 4: moderate CD, mild dementia. GDS 5: moderately severe CD, moderate dementia. GDS 6: severe CD, moderately severe dementia. GDS 7: very severe CD, severe dementia).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"13\" nameend=\"c13\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Cox regression model adjusted for the presence of neuropsychiatric subsyndromes clinically significant or relevant (that is, they have at least some neuropsychiatric symptoms with an NPI value\u0026thinsp;\u0026ge;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eAIC: 512.35\u003c/p\u003e \u003cp\u003eBIC: 515.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"13\" nameend=\"c13\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e2\u003c/sup\u003e Cox regression model adjusted for total NPI score\u003c/p\u003e \u003cp\u003eAIC: 513.88\u003c/p\u003e \u003cp\u003eBIC: 516.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn patients with dementia treated with PC, the NPSs influence institutionalization and mortality, with subsyndrome apathy (formed by symptoms of apathy and appetite alterations) being the most associated with both.\u003c/p\u003e \u003cp\u003eIn the 4 years of follow-up, one-third of the patients were institutionalized. The average duration from the start of the study until they entered a residence hall was 13 months. The annual incidence of institutionalization was 5.5 to 12 institutionalized per 100 person-years, which was higher in the first year than in the rest of the study period. Other studies carried out in specialized memory clinics in France and the Netherlands have reported a higher annual incidence of institutionalization, ranging from 11.8\u0026ndash;23.5% [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These differences may be related to sociocultural and economic factors that influence the decision to enter a family member in a residence, as well as the severity of dementia, since the published incidence is higher when the population has moderate\u0026ndash;severe dementia [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] than when other studies include only mild\u0026ndash;moderate dementia [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHalf of the patients died during the 4-year follow-up. The mean duration from the start of the study to death was 22 months. The annual incidence of mortality that we found in our study was 8.9 to 20.2 deaths/100 person-years, which was higher than that reported in other studies, which reported incidences ranging from 5.9\u0026ndash;7.4% [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The higher mortality in our study can be attributed to the greater severity of dementia, since these studies included only patients with mild\u0026ndash;moderate dementia and lowest average NPI score.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFactors associated with institutionalization\u003c/h2\u003e \u003cp\u003eIn our study, institutionalization was associated with the total NPI score and the presence of apathy subsyndrome when the symptoms are very intense. In other studies, highly symptomatic NPSs have also been described as predictors of patient institutionalization [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] In addition, high values on the NPI scale or a greater number of symptoms in patients have been reported [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The presence of apathy in patients with dementia has also been associated with a higher risk of admission to a residence, regardless of the burden of the caregiver [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], and this is especially notable for patients with early-onset dementia [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e] and those with Lewy body dementia [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. On the other hand, altered appetite, which is part of the apathy subsyndrome, has been described as a predictor of institutionalization along with other NPSs, although in only a few studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, we did not find a relationship between institutionalization and other NPSs or subsyndromes, in contrast to other studies in which an associations with agitation/aggressiveness [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], disinhibition [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], symptoms within the hyperactivity subsyndrome, and delusions and hallucinations, which are part of the psychosis subsyndrome [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and anxiety and depression (affective subsyndrome) were reported [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the other hand, we found that being male with a lower level of education and being in treatment for dementia were associated with institutionalization. A systematic review on the predictors of admission to residences in older people revealed that the results for both male sex and a low level of education or low income were inconsistent, with the strongest predictors being age, dementia or functional impairment [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. In a study carried out in Spain with people in a situation of dependency, the risk of institutionalization was three times higher among men than among women [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. However, in studies carried out in patients with dementia, there were no consistent results, since some studies have shown that the risk of institutionalization was greater among women [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e], whereas others showed this to be true among males [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith respect to the level in the studies, other authors have reported more institutionalization of patients with a higher level of education [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. These differences from the work we present may be due to the sociocultural context. In our population, although we could not collect data on the socioeconomic level of the patients, we consider that the level of the studies can be interpreted as a \"proxy\" of the economic level. A lower educational level would imply having fewer economic resources, which would limit the possibility of hiring external help to maintain care at home and could force institutionalization when the level of dependency increases and more time of care is needed. In this sense, in our case, the low level of education of the patients was associated caregiver overload in a previous work [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Managing behavioural symptoms can be difficult, and caregivers are sometimes unable to control the situation, which can lead to the institutionalization of patients [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. The presence of caregiver overload has been described in multiple studies as a predictor of institutionalization [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]; however, we have not been able to demonstrate such an association.\u003c/p\u003e \u003cp\u003eIn other studies, symptomatic treatments for NPSs, such as neuroleptics, have been shown to increase the risk of institutionalization [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], although in our case, we were not able to verify this association. In our study, we found that the specific treatment for dementia (anticholinesterase drugs and memantine) is related to admission to the hospital. Some anticholinesterase drugs (rivastigmine) are used to mitigate NPSs in patients with types of dementia in which neuroleptics are contraindicated, such as Lewy body dementia. The lack of control of the NPSs in these patients could cause institutionalization of the patient, which could be attributed to anticholinesterase drugs when, in reality, the theoretical cause could be the underlying NPS. Another possible explanation for the association between this drug group and institutionalization is the cholinergic side effects that these drugs cause, with interactions with other drugs that are used by these patients (for example, drugs for urinary incontinence), worsening the symptoms of cognitive deterioration. The findings in other studies are variable. One of them reported that patients who had received treatment before or within the year of diagnosis had a higher risk of admission to residences than did those without treatment; their interpretation was that patients without treatment were in earlier stages of the disease [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e], which could explain the association between anticholinesterase or memantine treatment and admission. However, other authors reported either that patients who were undergoing treatment had a lower risk of institutionalization [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e] or that there was no association between the two [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFactors associated with mortality\u003c/h2\u003e \u003cp\u003eRegarding the relationship between NPSs and mortality, the results revealed that a higher score on the NPI scale, which analyses the intensity of NPSs, is associated with mortality, which is consistent with the findings of other studies [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Among the different NPSs, only the presence of apathy syndrome was associated with mortality in our study. Apathy has been described as a predictor of mortality, as well as an isolated symptom [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e], as when it is part of the apathy subsyndrome (apathy and/or appetite disturbances) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Some authors suggest that this may be explained by the fact that apathy leads to a more serious clinical profile in Alzheimer's dementia patients, with worse functional progression and a higher risk of mortality [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]. A listless neurobehavioral profile also predicts death in patients with frontotemporal degeneration [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. In our study, we also found an association between mortality and the presence of psychotic symptoms (delusions and/or hallucinations), as in other studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], although this association could not be confirmed in the multivariate analysis. An association with agitation has been reported [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and one study reported no relationship between subsyndromes and mortality [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeuroleptic treatment in patients with dementia has been associated with mortality in several studies [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR78 CR79\" citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e]. In our case, we found an association only in the univariate analysis, as was the case with psychotic symptoms, which are usually treated with these drugs. Notably, the use of neuroleptics, especially those used for agitation and psychotic symptoms, was shown to be associated with a higher risk of cardiovascular events [\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e] and a higher risk of apathy [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e], both of which can increase mortality.\u003c/p\u003e \u003cp\u003eWith respect to other sociodemographic and clinical characteristics, mortality increased in older, more dependent patients and those with more severe dementia, which has been described in the literature as being associated with age [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e] and with disease severity [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, having more than two comorbidities measured with the Charlson index was associated with mortality. In people with dementia, comorbidities are frequent, cause an increase in disability, reduce the quality of life of the patient and the caregiver [\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e] and increase the risk of mortality [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]. There is no unanimity on how to analyse comorbidities in mortality studies. Although the Charlson index is one of the most widely used indices in the assessment of comorbidities [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], it does not include situations closely related to institutionalization or death among elderly individuals, such as hip fracture.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLimitations and strengths\u003c/h2\u003e \u003cp\u003e Although limited by geographical area, which may limit its external validity, the population included in our study has allowed us to carry out a prospective study of representative sample of patients with dementia in our region who live and are cared for in the community.\u003c/p\u003e \u003cp\u003eNeuropsychiatric symptoms can be analysed as isolated symptoms, as a group of symptoms or subsyndromes, with the global measure of the NPI scale, among other methods, which makes it difficult to compare studies. In this work, we have chosen some of the measures that best represent the NPSs, that is, the presence or absence of symptoms grouped into subsyndromes and the global values of the NPI scale in which the intensities of twelve NPSs are measured.\u003c/p\u003e \u003cp\u003eThis study has allowed us to provide evidence on the role that NPSs play in the institutionalization and survival of patients with dementia, with a method that allows us to provide better evidence on this problem and overcome some methodological limitations of some studies of dementia with which we can compare our results by proposing a prospective design with a 4-year follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eClinical and research applications\u003c/h2\u003e \u003cp\u003eFrom the perspective of PC, it is necessary to continue investigating the impact of NPSs on institutionalization and mortality, as well as on the quality of life of patients and caregivers by designing studies with larger sample sizes that consider sociocultural factors and monitor the possible biases that may occur in such a complex field due to the multiple interactions of different clinical and sociofamily circumstances.\u003c/p\u003e \u003cp\u003eNeurobehavioral characteristics could be useful for predicting survival [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. The study of apathy may be of special interest, with the development of more effective and user-friendly measurement tools in clinical practice that allow its early detection [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e] and differentiate it from depression to avoid unnecessary treatments. Although apathy has a neuropathological basis [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e], it can be associated with treatments such as neuroleptics [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]. These drugs are indicated in the management of other NPSs, such as delusions or agitation, when their intensity entails severe anguish to the patient and/or danger to the caregivers or the patients themselves, while reassessing their need from time to time [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan additionalcitationids=\"CR87\" citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]. Antidepressants have also been associated with worsening apathy over time [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e]. Investigating the periods of use of neuroleptics and other psychoactive drugs used to treat NPSs and observing their impact on the progression of the NPSs treated, on the appearance of new NPSs or on the triggering of therapeutic cascades may be helpful toward developing management strategies.\u003c/p\u003e \u003cp\u003eWe must also continue addressing the question regarding the most appropriate way to measure comorbidity in patients with dementia, evaluating possible groupings of diseases and/or drugs, which allows the design of indices or global measures that can be incorporated into the analyses to better explain the relationships between NPSs and institutionalization or mortality.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe institutionalization and mortality of patients with dementia treated in primary care are associated with the intensity of neuropsychiatric symptoms measured with the NPI scale and with the presence of apathy. Neuroleptics were associated with mortality, and anticholinesterase drugs and/or memantine were associated with institutionalization. Mortality was also associated with older age, severity of dementia, and greater comorbidity, whereas being male with a low educational level was a risk factor for institutionalization.\u003c/p\u003e \u003cp\u003eGiven the importance of apathy for both institutionalization and mortality, it seems appropriate to investigate adequate methods of early detection and management of this symptom that can improve the prognosis of patients and help caregivers. In the same way, it is important to see the role that the treatments used in dementia can have in the appearance and/or worsening of apathy, in the worsening of cognitive deterioration and in the secondary use of other drugs by causing therapeutic cascades. It is also advisable to implement training measures, for both health workers and caregivers, to help detect NPSs, provide guidance on their prevention and management, and avoid the initiation and/or prolongation of drug treatments when they are not necessary.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneuropsychiatric symptoms\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprimary care\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNPI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeuropsychiatric Inventory\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSTROBE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStrengthening the Reporting of OBservational studies in Epidemiology\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectronic health record\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlobal deterioration scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCognitive decline\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was carried out following the principles of the Declaration of Helsinki and its subsequent revisions and was approved by the Clinical Research Ethics Committee of the Alcorc\u0026oacute;n Foundation University Hospital on September 23, 2015 (for baseline analysis) and July 2, 2019 (for the follow-up study). Informed consent was requested from the caregivers responsible for the patients who were interviewed and, in the case of professional caregivers, from the legal representative of the patient. All caregivers were educated enough to read and understand the informed consent form. At the discretion of the responsible physician, consent was also requested from patients who were considered capable of providing it.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analysed during the current study are available from the corresponding author ([email protected]) upon reasonable request.\u003c/p\u003e\n\u003cp\u003eAll the data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received a grant for manuscript translation and publication from the Foundation for Research and Biomedical Innovation in Primary Care (FIIBAP) 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVG, MCH and IDC conceived the study. VG, MCH, JM and IDC contributed to the design. VG and MCH were responsible for the data collection. VG, MCH, JM and IDC analysed and interpreted the data. VG and MCH wrote the first draft of the manuscript. JM and IDC revised the manuscript and provided substantive contributions. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients and caregivers who agreed to participate in the study and the researchers Rosal\u0026iacute;a Delgado Puebla, Paula Garc\u0026iacute;a Domingo, Erika Hern\u0026aacute;ndez Melo and Javier L\u0026oacute;pez de Haro de Torres who participated in the initial data collection.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u0026apos; information (optional)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Victoria Garc\u0026iacute;a-Mart\u0026iacute;n (ORCID: https://orcid.org/0000-0002-1560-9842)\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePhD student in Epidemiology and Public Health at Universidad Rey Juan Carlos (Rey Juan Carlos University), Madrid, Spain.\u003c/li\u003e\n \u003cli\u003ePreventive Medicine and Public Health Service, Infanta Leonor-Virgen de la Torre University Hospital, Madrid, Spain.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;M Canto de Hoyos-Alonso (ORCID:https://orcid.org/0000-0002-1409-893X)\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePedro La\u0026iacute;n Entralgo Health Care Center, Alcorc\u0026oacute;n, Primary Care Management, Madrid Health Service, Madrid, Spain.\u003c/li\u003e\n \u003cli\u003eNetwork for Research on Chronicity, Primary Care and Health Promotion (RICAPPS), Spain\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;Jesus Martin Fernandez\u0026nbsp;(ORCID: https://orcid.org/0000-0001-9545-1549)\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eNetwork for Research on Chronicity, Primary Care and Health Promotion (RICAPPS), Spain.\u003c/li\u003e\n \u003cli\u003eFamily and Community Medicine Teaching Unit Oeste, Primary Care Management, Madrid Health Service, M\u0026oacute;stoles, Madrid, Spain.\u003c/li\u003e\n \u003cli\u003eDepartment of Medical Specialties and Public Health, Universidad Rey Juan Carlos (Rey Juan Carlos University), Alcorc\u0026oacute;n, Madrid, Spain\u003c/li\u003e\n \u003cli\u003eGregorio Mara\u0026ntilde;\u0026oacute;n Health Research Institute IiSGM\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;Isabel del Cura-Gonz\u0026aacute;lez (ORCID IdCG: 00002-3931-5304)\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eNetwork for Research on Chronicity, Primary Care and Health Promotion (RICAPPS), Spain.\u003c/li\u003e\n \u003cli\u003eDepartment of Medical Specialties and Public Health, Universidad Rey Juan Carlos (Rey Juan Carlos University), Alcorc\u0026oacute;n, Madrid, Spain\u003c/li\u003e\n \u003cli\u003eResearch Unit, Primary Care Management, Madrid Health Service, Madrid, Spain.\u003c/li\u003e\n \u003cli\u003eAgeing Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.\u003c/li\u003e\n \u003cli\u003eGregorio Mara\u0026ntilde;\u0026oacute;n Health Research Institute IiSGM\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNichols E, Steinmetz JD, Vollset SE, Fukutaki K, Chalek J, Abd-Allah F, et al. 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Course of neuropsychiatric symptoms during a 4-year follow up in the REAL-FR cohort. J Nutr Health Aging. 2012;16:134\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eTeipel SJ, Thyrian JR, Hertel J, Eichler T, Wucherer D, Michalowsky B, et al. Neuropsychiatric symptoms in people screened positive for dementia in primary care. Int Psychogeriatr. 2015;27:39\u0026ndash;48.\u003c/li\u003e\n \u003cli\u003eGort A, Mingot M, March J, G\u0026oacute;mez X, Soler T, Nicol\u0026aacute;s F. Utilidad de la escala de Zarit reducida en demencias. Med Clin (Barc). 2010;135:447\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eZarit SH, Reever KE, Bach-Peterson J. Relatives of the Impaired Elderly: Correlates of Feelings of Burden. Gerontologist. 1980;20:649\u0026ndash;55.\u003c/li\u003e\n \u003cli\u003eMart\u0026iacute;n M, Salvad\u0026oacute; I, Nadal S, Miji L, Rico J. Adaptaci\u0026oacute;n para nuestro medio de la escala de sobrecarga del cuidador (Caregiver Burden Interview) de Zarit. 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BMC Geriatr. 2023;23:1\u0026ndash;12.\u003c/li\u003e\n \u003cli\u003eDufournet M, Dauphinot V, Moutet C, Verdurand M, Delphin-Combe F, Krolak-Salmon P, et al. Impact of Cognitive, Functional, Behavioral Disorders, and Caregiver Burden on the Risk of Nursing Home Placement. J Am Med Dir Assoc. 2019;20:1254\u0026ndash;62.\u003c/li\u003e\n \u003cli\u003eBakker C, de Vugt ME, van Vliet D, Verhey FRJ, Pijnenburg YA, Vernooij-Dassen MJFJ, et al. Predictors of the time to institutionalization in young- versus late-onset dementia: results from the Needs in Young Onset Dementia (NeedYD) study. J Am Med Dir Assoc. 2013;14:248\u0026ndash;53.\u003c/li\u003e\n \u003cli\u003eBreitve MH, Br\u0026oslash;nnick K, Chwiszczuk LJ, Hynninen MJ, Aarsland D, Rongve A. Apathy is associated with faster global cognitive decline and early nursing home admission in dementia with Lewy bodies. Alzheimers Res Ther. 2018;10:1\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eLuppa M, Luck T, Weyerer S, K\u0026ouml;nig HH, Br\u0026auml;hler E, Riedel-Heller SG. Prediction of institutionalization in the elderly. A systematic review. Age Ageing. 2010;39:31\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003ePinz\u0026oacute;n-Pulido S, Garrido Pe\u0026ntilde;a F, Reyes Alc\u0026aacute;zar V, Lima-Rodr\u0026iacute;guez JS, Raposo Triano MF, Mart\u0026iacute;nez Domene M, et al. Factores predictores de la institucionalizaci\u0026oacute;n de personas mayores en situaci\u0026oacute;n de dependencia en Andaluc\u0026iacute;a. Enferm Clin. 2016;26:23\u0026ndash;30.\u003c/li\u003e\n \u003cli\u003eRunte R. Predictors of institutionalization in people with dementia: a survey linked with administrative data. Aging Clin Exp Res. 2018;30:35\u0026ndash;43.\u003c/li\u003e\n \u003cli\u003eJoling KJ, Janssen O, Francke AL, Verheij RA, Lissenberg-Witte BI, Visser PJ, et al. Time from diagnosis to institutionalization and death in people with dementia. Alzheimer\u0026rsquo;s \u0026amp; Dementia. 2020;16:662\u0026ndash;71.\u003c/li\u003e\n \u003cli\u003eHeyman A, Peterson B, Fillenbaum G, Pieper C. Predictors of time to institutionalization of patients with Alzheimer\u0026rsquo;s disease: The CERAD experience, Part XVII. Neurology. 1997;48:1304\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eHuang SW, Chang KH, Escorpizo R, Hu CJ, Chi WC, Yen CF, et al. Using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for Predicting Institutionalization of Patients With Dementia in Taiwan. Medicine. 2015;94:e2155.\u003c/li\u003e\n \u003cli\u003eCepoiu-Martin M, Tam-Tham H, Patten S, Maxwell CJ, Hogan DB. Predictors of long-term care placement in persons with dementia: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2016;31:1151\u0026ndash;71.\u003c/li\u003e\n \u003cli\u003eNational Institute for Health and Care Excellence (NICE). Dementia: Assessment, management and support for people living with dementia and their carers. London; 2018.\u003c/li\u003e\n \u003cli\u003eH\u0026eacute;bert R, Dubois MF, Wolfson C, Chambers L, Cohen C. Factors associated with long-term institutionalization of older people with dementia: Data from the Canadian study of health and aging. Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2001;56.\u003c/li\u003e\n \u003cli\u003eEska K, Graessel E, Donath C, Schwarzkopf L, Lauterberg J, Holle R. Predictors of Institutionalization of Dementia Patients in Mild and Moderate Stages: A 4-Year Prospective Analysis. Dement Geriatr Cogn Dis Extra. 2013;3:426\u0026ndash;45.\u003c/li\u003e\n \u003cli\u003eBlack CM, Fillit H, Xie L, Research S, Hu X, Furaha Kariburyo M. Economic Burden, Mortality, and Institutionalization in Patients Economic Burden, Mortality, and Institutionalization in Patients Newly Diagnosed with Alzheimer\u0026rsquo;s Disease Newly Diagnosed with Alzheimer\u0026rsquo;s Disease. Journal of Alzheimer\u0026rsquo;s Disease. 2018;61:185\u0026ndash;93.\u003c/li\u003e\n \u003cli\u003eLopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80:600.\u003c/li\u003e\n \u003cli\u003eBelger M, Haro JM, Reed C, Happich M, Argimon JM, Bruno G, et al. Determinants of time to institutionalisation and related healthcare and societal costs in a community-based cohort of patients with Alzheimer\u0026rsquo;s disease dementia. European Journal of Health Economics. 2019;20:343\u0026ndash;55.\u003c/li\u003e\n \u003cli\u003evan der Linde RM, Matthews FE, Dening T, Brayne C. Patterns and persistence of behavioural and psychological symptoms in those with cognitive impairment: the importance of apathy. Int J Geriatr Psychiatry. 2017;32:306\u0026ndash;15.\u003c/li\u003e\n \u003cli\u003eH\u0026ouml;ltt\u0026auml; EH, Laakkonen ML, Laurila J V., Strandberg TE, Tilvis RS, Pitk\u0026auml;l\u0026auml; KH. Apathy: Prevalence, Associated Factors, and Prognostic Value Among Frail, Older Inpatients. J Am Med Dir Assoc. 2012;13:541\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eVilalta-Franch J, Calv\u0026oacute;-Perxas L, Garre-Olmo J, Turr\u0026oacute;-Garriga O, L\u0026oacute;pez-Pousa S. Apathy syndrome in Alzheimer\u0026rsquo;s disease epidemiology: prevalence, incidence, persistence, and risk and mortality factors. J Alzheimers Dis. 2013;33:535\u0026ndash;43.\u003c/li\u003e\n \u003cli\u003eLansdall CJ, Coyle-Gilchrist ITS, V\u0026aacute;zquez Rodr\u0026iacute;guez P, Wilcox A, Wehmann E, Robbins TW, et al. Prognostic importance of apathy in syndromes associated with frontotemporal lobar degeneration. Neurology. 2019;92:E1547\u0026ndash;57.\u003c/li\u003e\n \u003cli\u003eL\u0026oacute;pez-Pousa S, Olmo JG, Franch JV, Estrada AT, Cors OS, Nierga IP, et al. Comparative analysis of mortality in patients with Alzheimer\u0026rsquo;s disease treated with donepezil or galantamine. Age Ageing. 2006;35:365\u0026ndash;71.\u003c/li\u003e\n \u003cli\u003eYeh T-C, Tzeng N-S, Li J-C, Huang Y-C, Hsieh H-T, Chu C-S, et al. Mortality Risk of Atypical Antipsychotics for Behavioral and Psychological Symptoms of Dementia. J Clin Psychopharmacol. 2019;39:472\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eConnors MH, Ames D, Boundy K, Clarnette R, Kurrle S, Mander A, et al. Predictors of Mortality in Dementia: The PRIME Study. J Alzheimers Dis. 2016;52:967\u0026ndash;74.\u003c/li\u003e\n \u003cli\u003eMaust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72:438\u0026ndash;45.\u003c/li\u003e\n \u003cli\u003eSacchetti E, Turrina C, Valsecchi P. Cerebrovascular accidents in elderly people treated with antipsychotic drugs: a systematic review. Drug Saf. 2010;33:273\u0026ndash;88.\u003c/li\u003e\n \u003cli\u003eTodd S, Barr S, Roberts M, Passmore AP. Survival in dementia and predictors of mortality: A review. Int J Geriatr Psychiatry. 2013;28:1109\u0026ndash;24.\u003c/li\u003e\n \u003cli\u003eLee M, Chodosh J. Dementia and Life Expectancy: What Do We Know? J Am Med Dir Assoc. 2009;10:466\u0026ndash;71.\u003c/li\u003e\n \u003cli\u003eFox C, Smith T, Maidment I, Hebding J, Madzima T, Cheater F, et al. The importance of detecting and managing comorbidities in people with dementia? Age Ageing. 2014;43:741\u0026ndash;3.\u003c/li\u003e\n \u003cli\u003ePeters ME, Rosenberg PB, Steinberg M, Tschanz JT, Norton MC, Welsh-Bohmer KA, et al. Prevalence of neuropsychiatric symptoms in CIND and its subtypes: The cache county study. American Journal of Geriatric Psychiatry. 2012;20:416\u0026ndash;24.\u003c/li\u003e\n \u003cli\u003eFrederiksen KS, Cooper C, Frisoni GB, Fr\u0026ouml;lich L, Georges J, Kramberger MG, et al. A European Academy of Neurology guideline on medical management issues in dementia. Eur J Neurol. 2020;27:1805\u0026ndash;20.\u003c/li\u003e\n \u003cli\u003eReus VI, Fochtmann LJ, Eyler AE, Hilty DM, Horvitz-Lennon M, Jibson MD, et al. The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia. Am J Psychiatry. 2016;173:543\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eHerrmann N, Lanct\u0026ocirc;t KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res Ther. 2013;5 Suppl 1:S5.\u003c/li\u003e\n \u003cli\u003eDonovan NJ, Wadsworth LP, Lorius N, Locascio JJ, Rentz DM, Johnson KA, et al. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. Am J Geriatr Psychiatry. 2014;22:1168\u0026ndash;79.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-geriatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bgtc","sideBox":"Learn more about [BMC Geriatrics](http://bmcgeriatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bgtc/default.aspx","title":"BMC Geriatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dementia, Incidence, Prognosis, Mortality, Institutionalization, Neuropsychiatric symptoms, Behavioural and psychological symptoms of dementia, Apathy, Neuropsychiatric Inventory, Primary care.","lastPublishedDoi":"10.21203/rs.3.rs-4765073/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4765073/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Neuropsychiatric symptoms (NPSs) are common in patients with dementia, but their associations with the risk of institutionalization and mortality are controversial. The objective of this study was to estimate the incidence of institutionalization and death among patients with dementia treated in primary care (PC) and to analyse the associations between NPSs and these events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This was a longitudinal analytical observational study of patients with dementia in PC with a 4-year follow-up. Data on sociodemographic, clinical and functional characteristics and prescribed treatments for dementia were collected. NPSs were examined with the Neuropsychiatric Inventory (NPI) scale and according to the presence of clinically relevant neuropsychiatric subsyndromes. The incidence of institutionalization and cumulative mortality were calculated annually and at 4 years. Survival analysis with Kaplan‒Meier curves and Cox regression was performed to analyse the influence of NPSs on institutionalization and mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 124 patients with a mean age of 82.5 (8.0) years were included, and 69.4% were women. At 4 years, the institutionalization rate in a nursing home was 29.8% (95% CI 22.0; 38.7), with a median time to institutionalization of 13.2 months (IQR: 6.8–31.5). The mortality rate was 48.4% (95% CI 39.3; 57.5), with a median survival time of 21.7 months (IQR: 14.2–32.0). The NPI score was associated with institutionalization (HR 1.27, 95% CI 1.12, 1.45) and mortality (HR 1.47, 95% CI 1.40, 1.54). Among the subsyndromes, the presence of clinically relevant apathy was associated with institutionalization (HR 2.23, 95% CI 1.29, 3.88) and mortality (HR 1.56, 95% CI 1.34, 1.81).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In patients with dementia treated in the community for four years of follow-up, one-third of the patients were institutionalized, and half died. The intensity of the NPSs influences both institutionalization and mortality, with subsyndrome apathy (formed by the symptoms of apathy and appetite alterations) being the one that most influences both outcomes.\u003c/p\u003e","manuscriptTitle":"Mortality and institutionalization of patients with dementia treated in primary care: Influence of neuropsychiatric symptoms (NeDEM project)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-16 00:38:53","doi":"10.21203/rs.3.rs-4765073/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision 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