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

doi:10.21203/rs.3.rs-4765073/v1

Download PDF

Research Article

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

https://doi.org/10.21203/rs.3.rs-4765073/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

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.

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.

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).

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)
				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

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.

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.

NPS

neuropsychiatric symptoms

primary care

NPI

Neuropsychiatric Inventory

STROBE

Strengthening the Reporting of OBservational studies in Epidemiology

EHR

Electronic health record

GDS

Global deterioration scale

Cognitive decline

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.
Gregorio Marañón Health Research Institute IiSGM

Nichols E, Steinmetz JD, Vollset SE, Fukutaki K, Chalek J, Abd-Allah F, et al. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7:e105–25.
Haibo X, Shifu X, Tze Pin N, Chao C, Guorong M, Xuejue L, et al. Prevalence and severity of behavioral and psychological symptoms of dementia (BPSD) in community dwelling Chinese: Findings from the Shanghai three districts study. Aging Ment Health. 2013;17:748–52.
Liew TM. Symptom Clusters of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Comparative Risks of Dementia: A Cohort Study of 8530 Older Persons. J Am Med Dir Assoc. 2019;20:1054.e1-1054.e9.
Thyrian JR, Eichler TS, Wucherer D, Dreier A, Teipel S, Hoffmann W. Behavioral and psychiatric symptoms in people with dementia in primary care. Alzheimer’s & Dementia. 2014;10:611.
Siafarikas N, Selbaek G, Fladby T, Šaltyte Benth J, Auning E, Aarsland D. Frequency and subgroups of neuropsychiatric symptoms in mild cognitive impairment and different stages of dementia in Alzheimer’s disease. Int Psychogeriatr. 2018;30:103–13.
García-Alberca JM, Pablo Lara J, González-Barón S, Barbancho MA, Porta D, Berthier M. Prevalence and comorbidity of neuropsychiatric symptoms in Alzheimer’s disease. Actas Esp Psiquiatr. 2008;36:265–70.
García-Martín V, de Hoyos-Alonso MC, Ariza-Cardiel G, Delgado-Puebla R, García-Domingo P, Hernández-Melo E, et al. Neuropsychiatric symptoms and subsyndromes in patients with different stages of dementia in primary care follow-up (NeDEM project): a cross-sectional study. BMC Geriatr. 2022;22:1–15.
Peters ME, Schwartz S, Han D, Rabins P V., Steinberg M, Tschanz JT, et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: The cache county dementia progression study. American Journal of Psychiatry. 2015;172:460–5.
Cooper C, Sommerlad A, Lyketsos CG, Livingston G. Modifiable predictors of dementia in mild cognitive impairment: A systematic review and meta-analysis. American Journal of Psychiatry. 2015;172:323–34.
Afram B, Stephan A, Verbeek H, Bleijlevens MHC, Suhonen R, Sutcliffe C, et al. Reasons for Institutionalization of People With Dementia: Informal Caregiver Reports From 8 European Countries. J Am Med Dir Assoc. 2014;15:108–16.
Tun SM, Murman DL, Long HL, Colenda CC, Von Eye A. Predictive validity of neuropsychiatric subgroups on nursing home placement and survival in patients with alzheimer disease. American Journal of Geriatric Psychiatry. 2007;15:314–27.
Cepoiu-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;31:1151–71.
Yaffe K, Fox P, Newcomer R, Sands L, Lindquist K, Dane K, et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA. 2002;287:2090–7.
Porter CN, Miller MC, Lane M, Cornman C, Sarsour K, Kahle-Wrobleski K. The influence of caregivers and behavioral and psychological symptoms on nursing home placement of persons with Alzheimer’s disease: A matched case–control study. SAGE Open Med. 2016;4:205031211666187.
Chen YJ, Wang WF, Jhang KM, Chang MC, Chang CC, Liao YC. Prediction of Institutionalization for Patients With Dementia in Taiwan According to Condition at Entry to Dementia Collaborative Care. Journal of Applied Gerontology. 2022;41:1357–64.
Luppa M, Luck T, Brähler E, König HH, Riedel-Heller SG. Prediction of institutionalisation in dementia: A systematic review. Dement Geriatr Cogn Disord. 2008;26:65–78.
Toot S, Swinson T, Devine M, Challis D, Orrell M. Causes of nursing home placement for older people with dementia: A systematic review and meta-analysis. International Psychogeriatrics. 2017;29:195–208.
Brodaty H, Connors MH, Xu J, Woodward M, Ames D. Predictors of institutionalization in dementia: A three year longitudinal study. Journal of Alzheimer’s Disease. 2014;40:221–6.
Park DG, Lee S, Moon YM, Na DL, Jeong JH, Park KW, et al. Predictors of Institutionalization in Patients with Alzheimer’s Disease in South Korea. J Clin Neurol. 2018;14:191.
Bränsvik V, Granvik E, Minthon L, Nordström P, Nägga K. Mortality in patients with behavioural and psychological symptoms of dementia: a registry-based study. Aging Ment Health. 2021;25:1101–9.
Russ TC, Batty GD, Starr JM. Cognitive and behavioural predictors of survival in Alzheimer disease: Results from a sample of treated patients in a tertiary-referral memory clinic. Int J Geriatr Psychiatry. 2012;27:844–53.
Huang MF, Lee WJ, Yeh YC, Lin YS, Lin HF, Wang SJ, et al. Neuropsychiatric symptoms and mortality among patients with mild cognitive impairment and dementia due to Alzheimer’s disease. Journal of the Formosan Medical Association. 2022;121:1705–13.
Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997;48 5 Suppl 6:S10-6.
Van Der Linde RM, Dening T, Matthews FE, Brayne C. Grouping of behavioural and psychological symptoms of dementia. Int J Geriatr Psychiatry. 2014;29:562–8.
Anatchkova M, Brooks A, Swett L, Hartry A, Duffy RA, Baker RA, et al. Agitation in patients with dementia: A systematic review of epidemiology and association with severity and course. Int Psychogeriatr. 2019;31:1305–18.
Rabins P V., Schwartz S, Black BS, Corcoran C, Fauth E, Mielke M, et al. Predictors of progression to severe Alzheimer’s disease in an incidence sample. Alzheimer’s and Dementia. 2013;9:204–7.
Villars H, Gardette V, Frayssignes P, Deperetti E, Perrin A, Cantet C, et al. Predictors of nursing home placement at 2 years in Alzheimer’s disease: A follow‐up survey from the THERAD study. Int J Geriatr Psychiatry. 2022;37.
Benoit M, Robert PH, Staccini P, Brocker P, Guerin O, Lechowski L, et al. One-year longitudinal evaluation of neuropsychiatric symptoms in Alzheimer’s disease. The REAL.FR Study. J Nutr Health Aging. 2005;9:95–9.
Wergeland JN, Selbæk G, Bergh S, Soederhamn U, Kirkevold Ø. Predictors for Nursing Home Admission and Death among Community-Dwelling People 70 Years and Older Who Receive Domiciliary Care. Dement Geriatr Cogn Dis Extra. 2015;5:320–9.
Hirono N, Tsukamoto N, Inoue M, Moriwaki Y, Mori E. Predictors of long-term institutionalization in patients with Alzheimer’s disease: Role of caregiver burden. Brain and Nerve. 2002;54:812–8.
De Vugt ME, Stevens F, Aalten P, Lousberg R, Jaspers N, Verhey FRJ. A prospective study of the effects of behavioral symptoms on the institutionalization of patients with dementia. Int Psychogeriatr. 2005;17:577–89.
Vandenbroucke JP, von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and Elaboration. PLoS Med. 2007;4:e297.
Cortes F, Nourhashémi F, Guérin O, Cantet C, Gillette-Guyonnet S, Andrieu S, et al. Prognosis of Alzheimer’s disease today: A two-year prospective study in 686 patients from the REAL-FR Study. Alzheimer & Dementia. 2008;4:22–9.
Gillette-Guyonnet S, Andrieu S, Nourhashemi F, Gardette V, Coley N, Cantet C, et al. Long-term progression of Alzheimer’s disease in patients under antidementia drugs. Alzheimer’s and Dementia. 2011;7:579–92.
Mahoney FI, Barthel DW. Functional evaluation: The Barthel Index. Md State Med J. 1965;14:61–5.
Shah S, Vanclay F, Cooper B. Improving the sensitivity of the Barthel Index for stroke rehabilitation. J Clin Epidemiol. 1989;42:703–9.
Reisberg B, Ferris SH, De Leon MJ, Crook T. The global deterioration scale for assessment of primary degenerative dementia. American Journal of Psychiatry. 1982;139:1136–9.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.
Hermansson J, Carlqvist P, Kennedy K, Pietri G. PRM4 Measuring Comorbidity in Administrative Data. Value in Health. 2011;14:A421.
de Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to measure comorbidity. a critical review of available methods. J Clin Epidemiol. 2003;56:221–9.
González Silva Y, Abad Manteca L, José Fernández-Gómez M, Martín-Vallejo J, de la Red Gallego José Luis Pérez-Castrillón H, Río Hortega Valladolid U. UTILITY OF THE CHARLSON COMORBIDITY INDEX IN OLDER PEOPLE AND CONCORDANCE WITH OTHER COMORBIDITY INDICES. 2021;14:64–70.
Vilalta-Franch, J, Lozano-Gallego, M, Hernández-Ferrándiz,M, Llinàs-Reglà,J, López-Pousa, S LO. Neuropsychiatric Inventory: propiedades psicométricas de su adaptación al español. Rev Neurol. 1999;29:15–9.
Aalten P, Verhey FRJ, Boziki M, Bullock R, Byrne EJ, Camus V, et al. Neuropsychiatric Syndromes in Dementia: Results from the European Alzheimer Disease Consortium - Part I. Dement Geriatr Cogn Disord. 2007;24:457–63.
Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of Neuropsychiatric Symptoms in Dementia and Mild Cognitive Impairment. JAMA. 2002;288:1475.
Steinberg M, Tschanz JT, Corcoran C, Steffens DC, Norton MC, Lyketsos CG, et al. The persistence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2004;19:19–26.
Selbæk G, Engedal K, Bergh S. The Prevalence and Course of Neuropsychiatric Symptoms in Nursing Home Patients With Dementia: A Systematic Review. J Am Med Dir Assoc. 2013;14:161–9.
Gonfrier S, Andrieu S, Renaud D, Vellas B, Robert PH. Course of neuropsychiatric symptoms during a 4-year follow up in the REAL-FR cohort. J Nutr Health Aging. 2012;16:134–7.
Teipel 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;27:39–48.
Gort A, Mingot M, March J, Gómez X, Soler T, Nicolás F. Utilidad de la escala de Zarit reducida en demencias. Med Clin (Barc). 2010;135:447–9.
Zarit SH, Reever KE, Bach-Peterson J. Relatives of the Impaired Elderly: Correlates of Feelings of Burden. Gerontologist. 1980;20:649–55.
Martín M, Salvadó I, Nadal S, Miji L, Rico J. Adaptación para nuestro medio de la escala de sobrecarga del cuidador (Caregiver Burden Interview) de Zarit. Revista de Gerontología. 1996;:338–45.
Christensen E. Multivariate survival analysis using Cox’s regression model. Hepatology. 1987;7:1346–58.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–26.
Wagenmakers EJ, Farrell S. AIC model selection using Akaike weights. Psychon Bull Rev. 2004;11:192–6.
Williams RL. A note on robust variance estimation for cluster-correlated data. Biometrics. 2000;56:645–6.
García-Martín V, de Hoyos-Alonso MC, Delgado-Puebla R, Ariza-Cardiel G, del Cura-González I. Burden in caregivers of primary care patients with dementia: influence of neuropsychiatric symptoms according to disease stage (NeDEM project). BMC Geriatr. 2023;23:1–12.
Dufournet 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;20:1254–62.
Bakker 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;14:248–53.
Breitve MH, Brønnick 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;10:1–8.
Luppa M, Luck T, Weyerer S, König HH, Brähler E, Riedel-Heller SG. Prediction of institutionalization in the elderly. A systematic review. Age Ageing. 2010;39:31–8.
Pinzón-Pulido S, Garrido Peña F, Reyes Alcázar V, Lima-Rodríguez JS, Raposo Triano MF, Martínez Domene M, et al. Factores predictores de la institucionalización de personas mayores en situación de dependencia en Andalucía. Enferm Clin. 2016;26:23–30.
Runte R. Predictors of institutionalization in people with dementia: a survey linked with administrative data. Aging Clin Exp Res. 2018;30:35–43.
Joling 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’s & Dementia. 2020;16:662–71.
Heyman A, Peterson B, Fillenbaum G, Pieper C. Predictors of time to institutionalization of patients with Alzheimer’s disease: The CERAD experience, Part XVII. Neurology. 1997;48:1304–9.
Huang 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.
Cepoiu-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;31:1151–71.
National Institute for Health and Care Excellence (NICE). Dementia: Assessment, management and support for people living with dementia and their carers. London; 2018.
Hébert 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.
Eska 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;3:426–45.
Black 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’s Disease Newly Diagnosed with Alzheimer’s Disease. Journal of Alzheimer’s Disease. 2018;61:185–93.
Lopez 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.
Belger 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’s disease dementia. European Journal of Health Economics. 2019;20:343–55.
van 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;32:306–15.
Hölttä EH, Laakkonen ML, Laurila J V., Strandberg TE, Tilvis RS, Pitkälä KH. Apathy: Prevalence, Associated Factors, and Prognostic Value Among Frail, Older Inpatients. J Am Med Dir Assoc. 2012;13:541–5.
Vilalta-Franch J, Calvó-Perxas L, Garre-Olmo J, Turró-Garriga O, López-Pousa S. Apathy syndrome in Alzheimer’s disease epidemiology: prevalence, incidence, persistence, and risk and mortality factors. J Alzheimers Dis. 2013;33:535–43.
Lansdall CJ, Coyle-Gilchrist ITS, Vázquez Rodríguez P, Wilcox A, Wehmann E, Robbins TW, et al. Prognostic importance of apathy in syndromes associated with frontotemporal lobar degeneration. Neurology. 2019;92:E1547–57.
López-Pousa S, Olmo JG, Franch JV, Estrada AT, Cors OS, Nierga IP, et al. Comparative analysis of mortality in patients with Alzheimer’s disease treated with donepezil or galantamine. Age Ageing. 2006;35:365–71.
Yeh 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;39:472–8.
Connors 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;52:967–74.
Maust 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;72:438–45.
Sacchetti E, Turrina C, Valsecchi P. Cerebrovascular accidents in elderly people treated with antipsychotic drugs: a systematic review. Drug Saf. 2010;33:273–88.
Todd S, Barr S, Roberts M, Passmore AP. Survival in dementia and predictors of mortality: A review. Int J Geriatr Psychiatry. 2013;28:1109–24.
Lee M, Chodosh J. Dementia and Life Expectancy: What Do We Know? J Am Med Dir Assoc. 2009;10:466–71.
Fox 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;43:741–3.
Peters 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;20:416–24.
Frederiksen KS, Cooper C, Frisoni GB, Frölich L, Georges J, Kramberger MG, et al. A European Academy of Neurology guideline on medical management issues in dementia. Eur J Neurol. 2020;27:1805–20.
Reus 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;173:543–6.
Herrmann N, Lanctôt 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.
Donovan 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;22:1168–79.

No competing interests reported.

Download PDF

Reviewers invited by journal
23 Sep, 2024
Editor invited by journal
20 Aug, 2024
Editor assigned by journal
07 Aug, 2024
Submission checks completed at journal
07 Aug, 2024
First submitted to journal
18 Jul, 2024

You are reading this latest preprint version

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

Status:

Version 1

Abstract

Figures

Background

Methods

Study design, setting and participants

Variables

Baseline data

Follow-up data

Statistical analysis

Ethics approval

Results

Institutionalization

Mortality

Discussion

Factors associated with institutionalization

Factors associated with mortality

Limitations and strengths

Clinical and research applications

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1