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International Psychogeriatrics (2015), 27:11, 1839–1847 C© International Psychogeriatric Association 2015 doi:10.1017/S1041610215000976

Association of neuropsychiatric symptoms and sub-syndromes with cognitive impairment in community-dwelling Asian elderly

...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Xin Xu,1,2 Seow Li Ang,1,2 Saima Hilal,1,2,3 Qun Lin Chan,1,2 Tien Yin Wong,4,5

Narayanaswamy Venketasubramanian,6 Mohammad Kamran Ikram1,4,5

and Christopher Li-Hsian Chen1,2 1 Memory Ageing and Cognition Centre (MACC), National University Health System, Singapore 2 Department of Pharmacology, National University of Singapore, Singapore 3 Department of Ophthalmology, National University of Singapore, Singapore 4 Singapore Eye Research Institute, Singapore National Eye Center, Singapore 5 Academic Medicine Research Institute, Duke-NUS Graduate Medical School, Singapore 6 Raffles Neuroscience Centre, Raffles Hospital, Singapore

A B S T RA C T

Objectives: To investigate the presence of neuropsychiatric symptoms (NPS) and sub-syndromes in elderly community-dwelling Asians with varying severity of cognitive impairment.

Methods: Chinese and Malay participants (n = 613) from the Epidemiology of Dementia in Singapore (EDIS) Study aged � 60 years underwent clinical examination, neuropsychological testing, and NPS assessment using the Neuropsychiatric Inventory (NPI). Diagnosis of no cognitive impairment (NCI), cognitive impairment-no dementia (CIND), including CIND-mild and CIND-moderate, and dementia were made using established criteria.

Results: A significant increase in the numbers of NPS was observed accompanying with increasing severity of cognitive impairment (p < 0.001). Compared to those with NCI/CIND-mild, participants with CIND- moderate [Odds ratio (OR): 4.2, 95% confidence interval (CI): 1.8–10.0] or dementia [OR: 9.2, 95% CI: 2.3–36.0] were more likely to have two or more neuropsychiatric sub-syndromes. Participants with CIND- moderate were more likely to have hyperactivity [OR: 2.0, 95% CI: 1.0–3.8] and apathy [OR: 2.9, 95% CI: 1.0–8.4] sub-syndromes, whereas patients with dementia were more likely to have psychosis [OR: 6.9, 95% CI: 2.4–20.1], affective (OR: 8.7, 95% CI: 1.8–42.9), and hyperactivity (OR: 5.4, 95% CI: 1.8–16.1). Furthermore, executive dysfunction and visual memory impairment were associated with the presence of three neuropsychiatric sub-syndromes; whist language and visuomotor speed impairment were related to the presence of two sub-syndromes. By contrast, impairment in attention, verbal memory, and visuoconstruction were not associated with any of the sub-syndromes.

Conclusions: The presence of NPS and sub-syndromes increase with increasing severities of cognitive impairment, and different neuropsychiatric syndromes are associated with specific impairment on cognitive domains in community-dwelling Asian elderly.

Key words: neuropsychiatric symptoms, sub-syndromes, community dwelling, Asian

Introduction

With rapidly aging populations, dementia has become a serious public health concern, particularly

Correspondence should be addressed to: Dr. Christopher Li- Hsian Chen, Department of Pharmacology, National University Health System, Clinical Research Centre, MD11, Level 5, #05-09, 10 Medical Drive, 117597, Singapore. Phone: + 65 65155885; Fax: + 65 68724101. Email: [email protected]. Received 9 Feb 2015; revision requested 18 Mar 2015; revised version received 26 May 2015; accepted 2 Jun 2015. First published online 23 July 2015.

in Asia (Catindig et al., 2012). Patients with dementia are reported to display more neuropsy- chiatric symptoms (NPS), which become more severe as the disease progresses (Lyketsos et al., 2000; Shinosaki et al., 2000). NPS in dementia significantly increase caregivers’ burden and are associated with earlier institutionlization and worse prognosis (Steele et al., 1990; Paulsen et al., 2000). In addition, NPS can have negative consequences for people with dementia, as these symptoms are

1840 X. Xu et al.

associated with poor quality of life for patients and their families, premature referral to institutional care, higher healthcare utilization, healthcare costs, and more rapid disease progression (Steele et al., 1990).

Furthermore, in the preclinical stages of dementia, such as cognitive impairment - no dementia (CIND), participants with NPS have a higher risk of converting to dementia (Beaudreau et al., 2013). However, most studies examining NPS in participants with cognitive impairment have mainly focused on Caucasian populations (Lyketsos et al., 2002; Tatsch et al., 2006; Geda et al., 2008; Okura et al., 2010; Peters et al., 2012; Beaudreau et al., 2013). In these populations, the cumulative prevalence of any NPS has been reported to be as high as 50% in participants with mild cognitive impairment (MCI) (Geda et al., 2008). Thus far, there are limited information available on the occurrences of NPS in participants with cognitive impairment in Asian populations (Ikeda et al., 2004; Muangpaisan et al., 2008; Feng et al., 2009; Chan et al., 2010; Haibo et al., 2013).

Moreover, there may be differing patterns of NPS in Asian populations as suggested by a Chinese study from Shanghai which reported a lower prevalence of NPS (Haibo et al., 2013). Apart from potential differences in pathophysiological mechanisms (e.g. specific brain areas that may be affected by neuronal loss, depositions of amyloid or tangles, cerebrovascular lesions) (Shinosaki et al., 2000), these variations in the prevalence and patterns of NPS may be due to diversity in the cultural background and psychosocial environment of study participants (Ikeda et al., 2004; Muangpaisan et al., 2008; Feng et al., 2009; Chan et al., 2010; Haibo et al., 2013). Furthermore, specific symptoms such as nighttime behaviors and changes in appetite/eating, have not been examined in previous studies (Ikeda et al., 2004; Feng et al., 2009); an omission which may be of importance as several studies have suggested that nighttime behaviors were one of the most commonly reported NPS in the elderly (Geda et al., 2004; Tatsch et al., 2006; Muangpaisan et al., 2008; Chan et al., 2010).

Finally, in recent years, it has been suggested that aggregating related NPS into sub-syndromes may have important advantages since sub-syndromes correspond to clinical observations (Cheng et al., 2012), could represent different underlying neuro- biological pathology (Kang et al., 2010), and may respond to particular treatments (Gauthier et al., 2005). Furthermore, there is evidence that sub- syndromes are stable across the course of dementia (Selbæk and Engedal, 2012) and are robust despite the use of different analytical methods (Aalten

et al., 2007). Although there are studies reporting on the prevalence of sub-syndromes in patients with dementia from memory clinics and nursing homes (Gauthier et al., 2005; Aalten et al., 2007; Kang et al., 2010; Cheng et al., 2012; Selbæk and Engedal, 2012), there have been no studies on sub- syndromes in community-dwelling elderly or in the preclinical stages of dementia.

In view of these gaps in knowledge, we examined in an Asian population of Chinese and Malay participants, the presence of NPS and sub-syndromes in different diagnostic groups, including no cognitive impairment (NCI), CIND, and dementia. We hypothesized that participants with more severe cognitive impairment would demonstrate a higher presence of NPS and sub- syndromes. We also hypothesized that impairment on specific cognitive domains would reveal distinctive association with the presence of neuropsychiatric sub-syndromes.

Methods

Sampling, screening, and procedure The EDIS study draws participants from the Singapore Epidemiology of Eye Disease (SEED) study, a multi-ethnic population-based study among persons aged 40 to 85 years among Chinese (Singapore Chinese Eye Study [SCES]), Malay (Singapore Malay Eye Study [SiMES-2]), and Indians (Singapore Indian Eye Study [SINDI-2]). For this study, we focused on the Chinese (Hilal et al., 2013) and Malay components (Rosman et al., 2012) of the EDIS Study, as the recruitment of the Indians is ongoing. In the first phase of the EDIS study, participants aged � 60 years (n = 2,666 Chinese and Malays) were screened using the Abbreviated Mental Test (Sahadevan et al., 2000) and a self-report of progressive forgetfulness (Chong et al., 2006). Screen-positive participants (n = 1,097) were invited to take part in the second phase of this study, which included an extensive neuropsychological test battery and brain MRI. Of these 1,097 participants, 623 agreed to participate in a second phase between August 2010 and December 2013 and hence were included in the present study. Of these, ten did not have a reliable informant and were excluded, leaving 613 participants (295 Chinese and 318 Malays) included in the final analysis. The details of the study methodology have been described elsewhere (Hilal et al., 2013). Ethics approval for EDIS study was obtained from the Singapore Eye Research Institute, and National Healthcare Group Domain- Specific Review Board. Written informed consent was obtained in the preferred language of the

Neuropsychiatric symptoms and syndromes in elderly 1841

participants by bilingual study coordinators prior to their recruitment into the study.

Neuropsychological assessment An extensive neuropsychological battery, which has been previously validated in Singaporean elderly, was administered to assess cognitive function (Hilal et al., 2013). The following seven domains were tested: Executive Function, Attention, Language, Visual Memory, Verbal Memory, Visuoconstruction, and Visuomotor speed.

Composite Z-scores for cognitive tests were generated based on the mean and standard deviation of the entire sample. Z-scores were derived for individual sub-tests, and Z-scores for individual domains were generated by summing up the Z-scores of each sub-test under that domain and dividing by number of sub-tests. A final global composite Z-score was computed using all domain specific Z-scores. Participants were considered to have failed a test if they scored lower than education-adjusted 1.5 standard deviations (SDs) below established normal means on each individual test. Failure in at least half of the tests in each domain was considered as impairment in that domain.

Assessment of NPS In addition to the above-mentioned neuropsycholo- gical battery, the 12-item NPI (Cummings, 1997) was administered to a reliable informant. The NPI is a structured interview which investigates the presence, frequency, severity, and caregiver distress in 12 behavioral domains, namely: (1) aberrant motor behaviors, (2) agitation, (3) anxiety, (4) apathy, (5) delusions, (6) depression, (7) disinhibition, (8) elation, (9) hallucinations, (10) irritability, (11) nighttime behaviors, and (12) eating/appetite change. For each domain, the informant is first asked a screening question as to whether the behavior has been present in the past month and if it represents a change from the participant’s usual behavior. If this is answered “yes,” additional questions are then asked. Informants are asked to rate the frequency of the symptoms in that domain (1 = occasionally; 2 = often; 3 = frequently; or 4 = very frequently or continuously), the severity of the symptoms (1 = mild; 2 = moderate; or 3 = severe), and the distress that they as caregivers experience in response to those symptoms (0 = not at all; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe; or 5 = very severe). A participant is considered as having a particular symptom when the screening question for a particular NPI item is answered “yes.” Presence

of NPS is defined as the presence of at least one of the symptoms in the NPI in the past month.

We classified NPS into four sub-syndromes as previously suggested by the European Alzheimer’s Disease Consortium (Aalten et al., 2007; 2008):

1. hyperactivity (agitation, elation, disinhibition, irritability, and aberrant motor behaviors),

2. psychosis (delusions, hallucinations, and nighttime behaviors),

3. affective symptoms (depression and anxiety), 4. apathy (apathy and appetite/eating change).

Presence of a sub-syndrome is defined as the presence of at least one of the symptoms in the sub- syndrome in the past month.

Sub-analysis was conducted using the current study sample to generate Principle Component Analysis (PCA) models for sub-syndromes and the results are consistent with the sub-syndrome model we adopted in our current study as mentioned above (data not shown).

Diagnosis of dementia Weekly consensus meetings were held with clinicians, neuropsychologists, clinical research fellows, research coordinators, and research assistants. Details from the clinical assessment, blood investigations, neuropsychological testing, and MRI scans were reviewed. NCI was diagnosed when participants were not impaired in any of the domains tested. The diagnosis of CIND was determined by clinical judgment and was anchored in the following guidelines, as previously published (Hilal et al., 2015): self and/or informant report of problems with cognition and impairment in at least one domain of the neuropsychological test battery using education-adjusted cut-offs of 1.5 SDs below established normal means within a domain, without any significant loss of independence in daily activities. CIND was classified into mild (when �2 domains were impaired) and moderate (when >2 domains were impaired). The diagnosis of dementia was made according to DSM-IV criteria (American Psychiatric Association, 1994).

Statistical analysis

The presence of NPS was compared among the following three groups: NCI/CIND-mild, CIND- moderate, and dementia. This categorization was used because it has been shown that participants with NCI and CIND-mild have a similar risk of converting to dementia, whereas those with CIND-moderate have a significantly higher risk of conversion (Narasimhalu et al., 2009). In order to compare characteristics, one-way analysis

1842 X. Xu et al.

Table 1. Demographic and clinical characteristics and neuropsychiatric data of participants

N C I / C I N D - C I N D - M I L D M O D E R A T E D E M E N T I A

( N = 370) ( N = 210) ( N = 33)

V A R I A B L E M E A N S D M E A N S D M E A N S D P (T R E N D ) .........................................................................................................................................................................................................................................................................................................................

Demographic and clinical characteristics

Age, years 68.6 5.8 73.5 6.6 78.8 5.2 <0.001 Education, years 6.4 4.3 3.1 3.5 1.9 2.9 <0.001 MMSE, total score 25.5 2.3 20.5 3.9 13.5 4.8 <0.001

N % N % N %

Gender, male 203 54.9 72 34.3 6 18.2 <0.001 Ethnicity, Chinese 210 56.8 78 37.1 7 21.2 <0.001

Presence of NPS Delusions 2 0.5 5 2.4 7 21.2 <0.001 Hallucinations 2 0.5 2 1.0 4 12.1 <0.001 Agitation 18 4.9 7 3.3 4 12.1 0.54 Depression 13 3.5 15 7.1 5 15.2 0.002 Anxiety 3 0.8 1 0.5 2 6.1 0.11 Elation 0 0.0 1 0.5 0 0.0 0.36 Apathy 3 0.8 6 2.9 5 15.2 <0.001 Disinhibition 3 0.8 2 1.0 2 6.1 0.07 Irritability 19 5.1 22 10.5 9 27.3 <0.001 Aberrant motor behaviors 0 0.0 3 1.4 5 15.2 <0.001 Nighttime behaviors 29 7.8 14 6.7 7 21.2 0.18 Eating/appetite change 6 1.6 11 5.2 2 6.1 0.01 At least one NPS 67 18.1 46 21.9 18 54.6 <0.001 At least two NPS 18 4.9 23 11.0 11 33.3 <0.001 At least three NPS 6 1.6 10 4.8 6 18.2 <0.001

of variance (ANOVA) was used for continuous variables and χ2 test for dichotomous variables. Test for trend analyses were performed to compare the presence of NPS and individual NPS domain among these three groups. We carried out multivariate logistic regression analyses to compare the presence of sub-syndromes among CIND-moderate groups and groups with dementia with NCI/CIND-mild and calculated OR together with corresponding 95% CI. Additional logistic regression models were employed to compare the presence of sub-syndromes among participants with impairment on cognitive domains with those who were unimpaired/ borderline on these domains. We adjusted the models for age, gender, ethnicity, and years of education. All analyses were performed with SPSS version 21 software and two-tailed p-value < 0.05 was considered statistically significant.

Results

A total of 613 participants were recruited in the EDIS study, of these 370 were NCI/CIND-mild, 210 had CIND-moderate and 33 had dementia. There were significant differences among the

three diagnostic groups in demography. The 30- day presence of NPS between participants with NCI/CIND-mild, CIND-moderate, and dementia was compared. On individual NPS domains, the presence of specific NPS increased from NCI/CIND-mild to CIND-moderate to dementia, including delusions, hallucinations, depression, apathy, irritability, aberrant motor behaviors, and eating/appetite change. (Table 1) Nevertheless, there was no ethnic difference between Chinese and Malays in the presence of NPS (data not shown).

Figure 1 shows that the number of NPS increased with increasing severity of cognitive impairment. Participants with two or more NPS increased significantly from NCI/CIND-mild to CIND-moderate to dementia (p < 0.001).

Figure 2 shows the type of sub-syndromes for each diagnostic group. The number of sub- syndromes increased from NCI/CIND-mild to CIND-moderate to dementia.

Table 2 shows that participants with CIND- moderate are more likely to demonstrate symptoms in the apathy (OR: 2.9, 95% CI: 1.0–8.4) and hyperactivity (OR: 2.0, 95% CI: 1.0–3.8) sub- syndromes but not in the psychosis (p = 0.85) and

Neuropsychiatric symptoms and syndromes in elderly 1843

1.6 4.8

18.2

3.2 6.2

15.2

13.2 11

21.2

81.9 78.1

45.5

0

20

40

60

80

100

NCI/CIND- mild CIND- moderate Dementia

Pe rc

en ta

ge o

f S ub

je ct

s R

ep or

ti ng

N eu

ro ps

yc hi

at ri

c Sy

m pt

om s

0 symptom

1 symptom

2 symptoms

≥3 symptoms

Figure 1. Total number of NPS in the past 30 days by diagnostic group (percentages are displayed in the graph).

7.8 12.4

36.4

8.6 8.6

39.4

4.1

7.1

15.2

1.9

6.7

15.2

0

20

40

60

80

100

NCI/CIND -mild CIND -moderate Dementia

Pe rc

en ta

ge o

f S ub

je ct

s R

ep or

ti ng

S ub

sy nd

ro m

es

Apathy

Affective

Psychosis

Hyperactivity

Figure 2. Presence of specific neuropsychiatric sub-syndrome in the past 30 days by diagnostic group (percentages are displayed in the

graph).

1844 X. Xu et al.

Table 2. Adjusteda odds ratios (ORs) by neuropsychiatric sub-syndrome

�1 S U B - �2 S U B - P S Y - A FF E C - H Y P E R - S Y N D R O M E S Y N D R O M E S C H O S I S T I V E A C T I V I T Y A P A T H Y

(n = 131) (n = 44) (n = 63) (N = 35) (n = 67) (n = 26)

O R 9 5 % C I O R 9 5 % C I O R 9 5 % C I O R 9 5 % C I O R 9 5 % C I O R ( 9 5 % C I ) .........................................................................................................................................................................................................................................................................................................................

Diagnosis: Comparing with NCI/CIND-mild

CIND-moderate 1.35 0.83–2.19 4.23 1.79–9.97 1.07 0.54–2.13 2.13 0.90–5.03 1.96 1.03–3.75 2.92 1.02–8.35 Dementia 5.45 2.18–13.6 9.16 2.33–35.98 6.88 2.36–20.07 8.73 1.78–42.87 5.42 1.83–16.09 4.62 0.80–26.85

Impairment on cognitive domains: Comparing with unimpaired/borderline Executive function 2.5 1.5–4.2 4.1 1.9–8.6 1.8 0.6–5.8 3.7 1.7–8.4 2.4 1.3–4.4 2.7 1.4–5.6 Attention 1.2 0.7–2.2 1.9 0.9–4.2 2.2 0.7–7.0 1.9 0.8–4.5 1.1 0.6–2.2 1.7 0.8–3.7 Language 1.8 0.9–3.7 2.9 1.2–6.9 5.0 1.5–16.4 1.5 0.5–4.7 2.7 1.2–5.9 1.6 0.6–4.1 Verbal memory 1.2 0.8–1.9 3.7 1.7–8.0 1.4 0.4–4.7 1.8 0.8–3.9 1.3 0.8–2.3 1.7 0.9–3.1 Visual memory 1.9 1.2–2.9 4.8 2.1–10.9 6.3 1.2–32.6 3.1 1.4–6.8 2.3 1.3–4.1 1.5 0.8–2.8 Visuoconstruction 1.4 0.9–2.3 3.1 1.3–7.1 1.4 0.4–5.7 2.0 0.9–4.4 1.8 1.0–3.3 1.4 0.8–2.8 Visuomotor speed 1.6 1.00–2.5 3.4 1.5–7.8 5.8 1.0–35.6 2.7 1.2–6.1 2.0 1.1–3.6 1.3 0.7–2.5

aORs were adjusted for age, years of education, gender, and ethnicity. Bold indicate significance.

affective (p = 0.08) sub-syndromes compared to NCI/CIND-mild participants.

By comparison, patients with dementia showed significant differences in affective (OR: 8.7, 95% CI: 1.8–42.9), hyperactivity (OR: 5.4, 95% CI: 1.8– 16.1), and psychosis (OR: 6.9, 95% CI: 2.4–20.1) sub-syndromes but not in the apathy sub-syndrome (p = 0.09) when compared to NCI/CIND-mild participants.

With respect to specific cognitive domains, executive dysfunction was associated with the presence of three sub-syndromes: affective (OR: 3.7, 95% CI: 1.7–8.4), hyperactivity (OR: 2.4, 95% CI: 1.3–4.4), and apathy (OR: 4.3, 95% CI: 1.4–5.6); Visual memory impairment was also associated with three sub-syndromes: psychosis (OR: 6.3, 95% CI: 1.2–32.6), affective (OR: 3.1, 95% CI: 1.4–6.8), and hyperactivity (OR: 2.3, 95% CI: 1.3–4.1). At the same time, language deficits were found to be related to two sub- syndromes: psychosis (OR: 5.0, 95% CI: 1.5– 16.4) and hyperactivity (OR: 2.7, 95% CI: 1.2– 5.9); Whilst visuomotor speed impairment was related to affective (OR: 2.7, 95% CI: 1.2–6.1) and hyperactivity (OR: 2.0, 95% CI: 1.1–3.6). By contrast, impairment in attention, verbal memory, and visuoconstruction domains was not associated with presence of any sub-syndrome. (Table 2)

Discussion

This study is the first to investigate the prevalence of neuropsychiatric sub-syndromes in community- dwelling Asian elderly and to relate the presence

of sub-syndromes with impairment on specific cognitive domains. We found that CIND-moderate participants had significantly more neuropsychiatric sub-syndromes, specifically greater odds of having hyperactivity and apathy sub-syndromes, compared to NCI/CIND-mild participants. This novel finding suggests that the study of sub-syndromes is equally important in participants with CIND as most previous studies have only reported on sub- syndromes in patients with dementia (Gauthier et al., 2005; Aalten et al., 2007; Kang et al., 2010; Cheng et al., 2012; Selbæk and Engedal, 2012). We have also found that patients with dementia were more likely to have psychosis, affective, and hyperactivity sub-syndromes compared to NCI/CIND-mild participants. This is in agreement with previous studies which have highlighted that psychosis, affective, and hyperactivity sub- syndromes are highly prevalent in patients with dementia (Aalten et al., 2007; 2008). Furthermore, we found that CIND-moderate participants were significantly more likely to display at least two sub- syndromes when compared to NCI/CIND-mild participants. Therefore, different patterns of sub- syndromes may be associated with the severity of cognitive impairment and hence be targets for earlier disease management and treatment. (Gauthier et al., 2005; Kang et al., 2010).

A novel finding is the association between the presence of certain sub-syndromes with impairment on specific cognitive domains. The current study shows that executive and visuomotor speed dysfunction is significantly associated with the presence of hyperactivity and affective syndromes. It has been suggested that executive and visuomotor

Neuropsychiatric symptoms and syndromes in elderly 1845

speed dysfunction is common in mania and depression which may reflect frontal cortex dysfunction (Marchand et al., 2005).

On the other hand, the presence of psychosis sub-syndrome, characterized by the presence of delusion, hallucination, and nighttime disturbance, is significantly associated with deficits on language and visual memory domains. Psychosis is common in schizophrenia, where there may also be underlying thalamic dysfunction. Such thalamic dysfunction could lead to disruption in the sensory gating system, and subsequently cause language production and memory retrieval problems. Interestingly, it has been reported that thalamic stimulation in schizophrenia improves speech production and reduces recalling errors (Johnson and Ojemann, 2000). Our finding hence may improve early detection and treatment of these neuropsychiatric sub-syndromes.

We compared the presence of NPS in our current study with other Asian (Ikeda et al., 2004; Feng et al., 2009; Chan et al., 2010; Haibo et al., 2013) and Western population-based studies (Lyketsos et al., 2002; Tatsch et al., 2006; Geda et al., 2008; Okura et al., 2010; Peters et al., 2012; Beaudreau et al., 2013): 17.9% of NCI participants and 54.5% of patients with dementia in our study demonstrated at least one NPS which is similar to both Asian- based (NCI: 5.9% to 29%, dementia: 50% to 88.3%) and Western-based studies (NCI: 15.1% to 25%, dementia: 57% to 80.1%). Hence, there is no difference in NPS prevalence in NCI and dementia populations.

However, we found a slightly lower presence (20.7%) of at least one NPS in Singaporean participants with CIND given that the prevalence rate in Western CIND/MCI participants ranges from 31% to 50% (Lyketsos et al., 2002; Tatsch et al., 2006; Geda et al., 2008; Okura et al., 2010; Peters et al., 2012; Beaudreau et al., 2013). One explanation to account for the variation in NPS is cultural differences as Asian societies tend to be conservative in nature, NPS may carry a social stigma (Wu et al., 2009). Hence, NPS might have been underreported. When compared to other Asian population-based studies which assessed CIND/MCI participants, we observed a lower presence of participants with at least one NPS in this study when compared to Hong Kong (36.7%) (Chan et al., 2010) but a higher presence when compared to a previous Singaporean community- based study (12.9%) (Feng et al., 2009). A possible reason to explain the former is selection bias as only participants who had subjective cognitive complaints were recruited into the present study. The difference with the latter study may be due to nighttime behaviors, which was observed to be

highly prevalent in the current study but were not assessed in the earlier study (Feng et al., 2009).

Nevertheless, we found a graded increase in NPS with increasing severity of cognitive impairment in that the number of participants having at least two NPS or at least three NPS increased significantly from NCI/CIND mild to CIND moderate to dementia. These results support the findings from a previous study in Caucasian population (Okura et al., 2010). We have extended this to an Asian population hence emphasizing the global importance of NPS in populations with increasing severity of cognitive impairment.

Interestingly, across all groups in the current study, irritability was identified to be one of the most prevalent symptoms. Affective symptoms, particu- larly irritability, had been frequently reported to be present in CIND participants in earlier community- based studies (14.7% (Lyketsos et al., 2002) to 19.4% (Geda et al., 2008)). Similarly, nighttime behaviors was also observed to be one of the most prevalent symptoms across all groups. An earlier study (Peters et al., 2013) had highlighted that NPS, in particular nighttime behaviors was a risk factor for dementia. Furthermore, a tertiary center study (Geda et al., 2004) reported that nighttime behaviors (7.7%, 16.7%) and irritability (2.1%, 12.9%) were the most common symptoms in NCI and MCI participants respectively, similar to the current study.

A limitation to our study is that 43.2% of the screened positive participants did not participate in the second phase of the study. Since these participants were older and as older participants showed more NPS (Steinberg et al., 2006), there may be an underestimation of the presence of NPS in our current study. As the comparison of Asian countries’ prevalence rates is based on a limited number of Asian studies, further studies are needed to confirm whether there is a difference in NPS prevalence rates when compared with other population-based studies. In addition, future studies should be conducted to assess cultural differences in the presence of NPS across more dissimilar ethnicities, e.g. Caucasians versus Asians.

In conclusion, we have confirmed in an elderly Asian population, there is an increasing frequency of NPS with increasing severity of cognitive impairment, thus emphasizing the importance of NPS in patients with cognitive impairment. A novel finding is that the number and type of sub- syndromes are associated with severity of cognitive impairment and specific impairments on cognitive domains. Our study confirms that NPS and sub- syndromes are associated with various severity and types of cognitive impairment. Hence, they may be important targets for treatment.

1846 X. Xu et al.

Conflict of interest

None.

Description of authors’ roles

X. Xu designed the study, collected the data, conducted statistical analysis, interpreted data, and drafted the paper. S. L. Ang designed the study, collected the data, conducted statistical analysis, interpreted data, and revised the paper. S. Hilal collected the data and revised the paper. Q. L. Chan was responsible for the collection of data. T.Y. Wong revised the paper. N. Venketasubramanian was responsible for supervising and revising the paper. M. K. Ikram was responsible for the study design, supervision, and revision of the paper. C. L. Chen designed the study, supervised statistical analysis, interpreted data, and was responsible for the critical revision of the paper.

Acknowledgments

The authors thank all staff and participants of the EDIS Study and the SEED Study for their important contributions. The EDIS study is supported by the National Medical Research Coun- cil (NMRC), Singapore (NMRC/CG/NUHS/2010 [Grant no.: R-184-006-184-511]). Additional funding was received from the Singapore Ministry of Health’s National Medical Research Council (NMRC/CSA/038/2013). The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

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