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Prevalence of neuropsychiatric syndromes in Alzheimer's disease (AD)
Archives of Gerontology and Geriatrics 52 (2011) 258–263
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Prevalence of neuropsychiatric syndromes in Alzheimer’s disease (AD) Jong Chul Youn a, Dong Young Lee b, Jin Hyeong Jhoo c, Ki Woong Kim d, Il Han Choo b, Jong Inn Woo b,* a
Department of Neuropsychiatry, Kyunggi Provincial Hospital for the Elderly, Yongin, Kyunggi-do 449-769, Republic of Korea Department of Neuropsychiatry, Seoul National University College of Medicine and Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea c Department of Neuropsychiatry, Kangwon National University College of Medicine and Kangwon National University Hospital, Chuncheon, 200-722 Kangwon-do, Republic of Korea d Department of Neuropsychiatry, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Sungnam, Kyunggi-do 463-707, Republic of Korea b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 April 2009 Received in revised form 18 April 2010 Accepted 19 April 2010 Available online 26 May 2010
This study aimed to estimate the prevalence and explore the multidimensional complexity of the neuropsychiatric syndromes of AD. Neuropsychiatric symptoms and syndromes of 216 subjects with probable and possible AD diagnosed by NINCDS-ADRDA criteria were evaluated by the Korean version of behavior rating scale for dementia (BRSD-K). The prevalence rate of six neuropsychiatric syndromes (depressive symptoms, inertia, vegetative symptoms, irritability/aggression, behavioral dysregulation, psychotic symptoms) and comorbid neuropsychiatric syndromes were calculated according to the Clinical Dementia Rating scale. To investigate the relationship among neuropsychiatric syndromes, logistic regression analyses were performed. About 95% of patients with AD had one or more neuropsychiatric symptoms and syndromes during the past month. Among the neuropsychiatric syndromes, irritability/aggression (76.2%) was the most frequent, followed by apathy (72.3%) and depressive symptoms (68.0%). About 90% of the subjects had one or more comorbid neuropsychiatric syndromes. The mean numbers of comorbid neuropsychiatric syndromes were significantly varied according to the severity of disease (p < 0.05). Depressive symptoms were significantly associated with vegetative symptoms and irritability/aggression (p < 0.05). Inertia and psychotic symptoms were significantly associated with vegetative symptoms and behavioral dysregulation, respectively (p < 0.05). This study demonstrated that neuropsychiatric syndromes of AD were highly prevalent and involved complex relationships among them. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Alzheimer’s disease Neuropsychiatric symptom Neuropsychiatric syndrome Comorbidity Behavior rating scale for dementia
1. Introduction Neuropsychiatric symptoms should be regarded as one of the central symptoms of AD. They have been associated with a greater degree of cognitive impairment (Jeste et al., 1992; Perez-Madrinan et al., 2004), rapid disease progression (Mortimer et al., 1992; Stern et al., 1997), caregiver burden (Rabins et al., 1982; Dunkin and Anderson-Hanley, 1998) and early institutionalization (Steele et al., 1990; O’Donnell et al., 1992). Neuropsychiatric symptoms of AD are not a unitary concept (Robert et al., 2005). They include a very wide range of individual symptoms. The prevalence estimates of these varied, from 60% to 90%, mainly as a result of differences in the evaluation method and clinical characteristics of the study sample (Mack et al., 1999; Lyketsos et al., 2002; McKeith and Cummings, 2005). Because neuropsychiatric symptoms of AD were closely linked
* Corresponding author. Tel.: +82 2 2072 2456; fax: +82 2 2072 3176. E-mail address: [email protected] (J.I. Woo). 0167-4943/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2010.04.015
with one or more other symptoms, a syndromatic approach which conceptualized the neuropsychiatric symptoms of AD as constellations of several syndromes like depression, psychosis and agitation (Harwood et al., 1998; Mack et al., 1999; Aalten et al., 2007) has an advantage in identifying the biological correlates and estimating the treatment response (Robert et al., 2005; Aalten et al., 2007). Based on the results of studies using this approach, several others proposed a classification system of neuropsychiatric symptoms of AD (Lyketsos et al., 2001a,b; Robert et al., 2005). However, several issues regarding neuropsychiatric syndromes of AD should be further investigated. For example, the prevalence of neuropsychiatric syndromes of AD has been rarely investigated (Aalten et al., 2007). In spite of the evidence that neuropsychiatric syndromes of AD are not likely to appear alone and most likely to occur with other syndromes (Dechamps et al., 2008), interrelationships among the neuropsychiatric syndromes of AD have rarely been examined. Thus, this study aimed to estimate the prevalence and explore the multidimensional complexity of the neuropsychiatric syndromes of AD.
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2. Subjects and methods
Table 1 Demographic and clinical characteristics of study subjects.
2.1. Subjects Two hundred sixteen subjects with probable and possible AD, according to the NINCDS-ADRDA criteria (McKhann et al., 1984), were enrolled from two special dementia clinics: the Seoul National University Hospital and Kyunggi Provincial Hospital for the Elderly. Most subjects were community dwellers at the time of behavioral evaluation. On entry into the study, informed consent was obtained from patients or their family caregivers according to the guidelines issued by the institutional review boards of the hospitals involved. All participants were evaluated in accordance with the clinical assessment protocol of the Korean version of CERAD (CERAD-K) (Lee et al., 2002). Severity of dementia was evaluated using the clinical dementia rating (CDR) scale (Hughes et al., 1982). Final diagnosis and severity were assigned by a consensus panel comprised of at least four geriatric psychiatrists with expertise in dementia research after reviewing the available neuropsychological test results and neuroimaging data. Although medications were not controlled during this study, most of the subjects were evaluated before taking any medication to reduce BPSD. Subjects without a reliable informant were excluded from the study. 2.2. Behavioral assessment Neuropsychiatric symptoms and syndromes were evaluated by the Korean version of the behavior rating scale for dementia (BRSDK) which consists of 46 questions related to the neuropsychiatric symptoms of AD (Tariot et al., 1995; Youn et al., 2008). Thirty-eight items of the 46 items were scaled by frequency with possible ratings as follows: 0 = not occurred since illness began; 1 = present 1–2 days in the past month; 2 = present 3–8 days in the past month; 3 = present 9–15 days in the past month; 4 = present 16 days or more in the past month; 8 = occurred since illness began but not in during the past month; 9 = unable to rate. To calculate the prevalence of clinically relevant neuropsychiatric symptoms, a symptom was recorded as present if symptoms were present at least 3 days within the past month. The remaining eight items (items 9, 10, 12, 14, 5, 17, 26, 32) were framed relative to ‘‘before dementia began’’ and were rated as present or absent. The presence of six neuropsychiatric syndromes (depressive symptoms, inertia, vegetative symptoms, irritability/aggression, behavioral dysregulation, psychotic symptoms), which were included as subscales in BRSD-K, were rated as being present when any items in the subscales were rated as present in the previous month. The BRSD-K was administered within 3 months of a CERAD evaluation for each subject. 2.3. Statistical analysis Frequencies of neuropsychiatric symptoms and syndromes of AD, according to the severity of disease, were calculated. Frequencies of comorbid neuropsychiatric symptoms and syndromes were also calculated. To evaluate the likelihood that subjects exhibiting one neuropsychiatric syndrome would also exhibit another neuropsychiatric syndrome, forward logistic regression analyses using age, sex, education, APOE genotype and CDR score as independent variable were performed. All statistical analyses were performed by SPSS 11.0. 3. Results 3.1. Demographic and clinical characteristics of the subjects The age of the subjects ranged from 48 to 98 years, with a mean age of 72.9 9.9 years. About 70% of the subjects were female. While
259
Number
Mean S.D.
Age (years) Female Education (years)
216 216 216
72.9 9.9
Diagnosis Probable AD Possible AD
216
CDR 0.5 1 2 3
216
Duration of illness (years) MMSE Blessed ADL
205 172 216
n (%) 150 (69.4)
6.3 5.7 144 (66.7) 72 (33.3)
30 90 61 35
(13.9) (41.7) (28.2) (16.2)
4.1 2.5 14.4 6.0 6.0 3.9
mean education years was relatively low (6.3 5.7), there was a broad range in years of school completed (0–20). Diagnosis of probable AD was 66.7%. More than half of subjects had dementia below the mild level of severity. Thirty subjects had CDR 0.5; 90 subjects, CDR 1; 61 subjects, CDR 2; 35 subjects, CDR 3. A total 172 subjects completed the MMSE and the mean score was 14.4 2.5. Most of the informants lived with the study subjects (81%) and were the spouse (37.5%) or children (33.8%) of the subjects (Table 1). 3.2. Prevalence of neuropsychiatric symptoms and syndrome Nearly all (96.3%) of the subjects had one or more neuropsychiatric symptom during the past month. The frequencies of neuropsychiatric symptoms ranged from 1.9% (item 35, misidentification of objects; item 39, belief that the caregiver is an imposter) to 70.4% (item 30, verbal repetitiveness) (Table 2). Neuropsychiatric symptoms of AD with the highest frequencies were, in decreasing order, verbal repetitiveness (70.4%), loss of enjoyment (51.9%), irritability (44.9%), loss of initiative (41.2%) and tiredness (36.1%). In line with neuropsychiatric symptoms, 94.4% subjects had one or more neuropsychiatric syndromes. Inertia (70.4%) was the most frequent, followed by irritability/aggression (67.3%), depressive symptoms (54.2%), behavioral dysregulations (51.4%) and psychotic symptoms (25.0%) (Table 3). Frequencies of neuropsychiatric symptoms and syndromes were varied according to the severity of disease. Among 45 items, frequencies of 20 neuropsychiatric symptoms were significantly different with respect to the severity of AD (p < 0.05). Frequencies of most neuropsychiatric symptoms peaked in moderate to severe stages of AD other than two symptoms (item 9, loss of enjoyment; item 31, social withdrawal) both of which had their highest frequencies in mild level of disease severity. Frequencies of all neuropsychiatric syndromes except vegetative symptom were significantly different in relation to the severity of disease (p < 0.05) and the highest was observed in moderate to severe stages. Inertia showed the highest frequency in mild stages. 3.3. Comorbid neuropsychiatric symptoms and syndromes Most of the study subjects (92.1%) had two or more neuropsychiatric symptoms and the mean number of neuropsychiatric symptoms per individual was 9.0 6.6. A large percentage of the subjects (85.5%) also had one or more comorbid neuropsychiatric syndrome with a mean number of comorbid syndrome per individual of 3.1 1.7. The mean number of comorbid neuropsychiatric symptoms and syndromes also varied significantly according to the severity of disease (F = 6.72, df = 3, p = 0.001 for neuropsychiatric symptom; F = 8.64, df = 3, p = 0.001 for neuropsychiatric syndrome).
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Table 2 Prevalence of individual neuropsychiatric symptoms in AD. Item 1. Feeling of anxiety 2. Physical sign of anxiety 3. Sad appearance 4. Feeling of hopelessness 5. Crying 6. Felling of guilt 7. Poor self-esteem 8. Wish to die 9. Loss of enjoyment 10. Loss of initiative 11. Tiredness 12. Altered sleep pattern 13.Trouble in sleeping 14. Change in appetite 15. Change in weight 16.Excessive complaints 17. Change in sexual drive 18. Sudden changes in emotion 19. Agitation 20. Irritability 21. Uncooperativeness 22. Verbal aggression 23. Physical aggression 24. Restlessness 25. Purposeless behavior 26. Diurnal pattern of confusion 27. Purposeless wandering 28. Attempts to leave resid. 29. Socially inappropriate behavior 30. Verbal repetitiveness 31. Social withdrawal 32. Attention seeking 33. Misidentific. of people 34. Misidentific. of self 35. Misidentific. of objects 36. Belief: is being hared 37. Belief: spouse unfaithful 38. Belief: being abandoned 39. Belief: caregiver imposter 40. Belief: TV characters are real 41. Belief: people in house 42. Belief: deads alive 43. Belief: house is not home 44. Auditory hallucination 45. Visual hallucination
Total 26.4 30.6 35.6 21.3 21.3 5.6 12.0 12.0 51.9 41.2 36.1 30.1 19.9 20.8 14.8 17.1 6.9 6.9 23.6 44.9 36.6 20.4 8.3 27.8 36.1 18.1 15.7 11.1 13.4 70.4 31.5 34.3 10.2 3.7 1.9 21.3 4.2 5.1 1.9 7.9 8.3 7.9 11.6 7.4 6.5
CDR0.5
CDR1
16.7 20.0 30.0 13.3 23.3 3.3 10.0 6.7 16.7 26.7 23.3 20.0 13.3 20.0 3.3 6.7 3.3 10.0 6.7 26.7 16.7 6.7 0 6.7 20.0 6.7 3.3 0 3.3 66.7 66.7 13.3 0 0 0 13.3 0 0 3.3 0 0 0 0 0 0
CDR2
26.7 36.7 40.0 28.9 15.6 3.3 17.8 13.3 66.7 47.8 40.0 28.9 18.9 16.7 20.0 22.2 4.4 4.4 23.3 46.7 37.8 18.9 5.6 24.4 28.9 10.0 10.0 6.7 11.1 77.8 77.8 32.2 6.7 0 1.1 26.7 5.6 4.4 2.2 2.2 5.6 4.4 5.6 4.4 5.6
The mean number of comorbid neuropsychiatric symptoms was 4.7 4.8 in CDR 0.5, 8.98 6.1 in CDR 1, 11.09 6.77 in CDR 2, 9.11 6.6 in CDR 3 (Fig. 1A). The mean number of comorbid neuropsychiatric syndromes was 1.8 1.5 in CDR 0.5, 3.1 1.6 in CDR 1, 3.6 1.6 in CDR 2, 3.3 1.8 in CDR 3 (Fig. 1B). Results of Turkey-b post hoc test shows that subjects with CDR 0.5 had a smaller number of comorbid neuropsychiatric symptoms and syndromes than subjects with other stages.
37.7 31.1 36.1 19.7 29.5 9.8 11.5 13.1 55.7 42.6 36.1 34.4 18.0 24.6 8.2 16.4 13.1 3.3 37.7 52.5 44.3 27.9 14.8 34.4 49.2 32.8 24.6 16.4 23.0 78.7 78.7 52.5 16.4 6.6 1.6 21.3 6.6 11.5 0 14.8 13.1 13.1 21.3 9.8 6.6
CDR3
p < 0.05
14.3 22.9 28.6 11.4 20.0 5.7 0 11.4 37.1 34.3 37.1 34.3 31.4 25.7 22.9 14.3 5.7 17.1 14.3 42.9 37.1 22.9 11.4 42.9 45.7 22.9 25.7 22.9 11.4 40.0 40.0 25.7 17.1 11.4 5.7 14.3 0 0 2.9 17.1 14.3 14.3 20.0 17.1 14.3
*
*
* *
* * * * * * * * * *
*
*
* * * *
3.4. Relationships among neuropsychiatric syndromes The relationships among the neuropsychiatric syndromes evaluated by regression analysis were presented in Table 4. Irritability/aggression is associated with depression, vegetative symptoms and behavioral dysregulation. Psychosis was associated with depression and behavioral dysregulation. Among the clinical and demographic variables, education was associated with apathy
Table 3 Prevalence of neuropsychiatric syndromes of Alzheimer’s disease, n (%). Total
Number Depressive symptoms Inertia Vegetative symptoms Irritability/aggression Behavioral dysregulation Psychotic symptoms No neuropsychiatric syndrome
117 152 101 140 111 54 12
(54.2) (70.4) (46.8) (67.3) (51.4) (25.0) (5.6)
Severity CDR 0.5
CDR 1
CDR 2
CDR3
30 14 12 9 13 7 0 5
90 52 74 43 60 35 14 4
61 37 42 32 45 43 25 2
35 14 24 17 22 26 15 1
(46.7) (40.0) (30.0) (43.3) (23.3) (16.7)
(57.8) (82.2) (47.8) (66.7) (38.9) (15.6) (4.4)
(60.7) (68.9) (52.5) (73.8) (70.5) (41.0) (3.3)
Notes: all items show a significance of p < 0.05 by x2 analysis (except the vegetative symptoms) according to the severity of dementia.
(40.0) (68.6) (48.6) (62.9) (74.3) (42.9) (2.9)
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261
Fig. 1. Frequencies of comorbid neuropsychiatric symptoms (A) and syndromes (B) according to severity of Alzheimer’s disease.
and behavioral dysregulation and CDR score was associated with psychotic symptoms. 4. Discussion This study demonstrated that neuropsychiatric symptoms and syndromes of AD were highly prevalent and inter-correlated. In this study, about 90% of AD patients had comorbid neuropsychiatric symptoms. Because neuropsychiatric symptoms are inter-correlated (Lyketsos et al., 2002), several studies have attempted to classify the neuropsychiatric symptoms of AD into 3–6 neuropsychiatric syndromes, both statistically and conceptually (Lyketsos et al., 2001a,b; Aalten et al., 2007). Although this syndromatic approach could help to identify the subgroups of AD patients with different symptom complexes which might reflect a different prevalence, progression, biological correlates and treatment response (Lyketsos et al., 2001a,b), the results of this study showed that individual neuropsychiatric syndromes of AD were not independent from each other. In this Table 4 Relationships among the neurobehavioral syndromes of AD.a.
b
OR (95%CI)
p<
Depressive symptoms Irritability Psychotic symptoms
0.83 1.14
2.29 (1.18–4.47) 3.14 (1.40–7.01)
0.015 0.005
Inertia Education Vegetative symptoms
0.07 1.63
1.07 (1.02–1.14) 5.08 (2.31–11.12)
0.044 0.0001
Vegetative symptoms Inertia Psychotic symptoms Irritability
1.31 0.84 0.87
3.71 (1.69–8.17) 2.32 (1.06–5.09) 2.39 (1.18–4.87)
0.001 0.036 0.016
Irritability/aggression Depressive symptoms Vegetative symptom Dysregulation
0.86 0.910 1.73
2.36 (1.15–4.85) 2.48 (1.19–5.19) 5.65 (2.62–12.16)
0.019 0.015 0.001
Behavioral dysregulation Irritability Psychotic symptoms Education
1.89 2.53 0.07
6.58 (2.85–15.2) 12.55 (4.00–39.3) 0.93 (0.87–0.99)
0.001 0.001 0.032
Psychotic symptoms CDR rating Depressive symptoms Behavioral dysregulation
1.37 1.57 2.44
3.94 (2.04–7.62) 4.79 (1.77–12.96) 11.48 (3.61–36.46)
0.001 0.002 0.001
a
Age, sex, education, APOE and CDR rating were used as independent variables.
study, about 85% of AD subjects had two or more neuropsychiatric syndromes. This result was consistent with the results of previous studies focused to the overlapping among the neuropsychiatric syndromes of AD (Tractenberg et al., 2003; Dechamps et al., 2008). One nursing home study for 109 subjects with dementia reported that about 85% of the dementia subjects had one or more neuropsychiatric syndrome (Dechamps et al., 2008). In the other community study, which targeted three neuropsychiatric syndrome, 82% of subjects with AD had two or more neuropsychiatric syndromes (Tractenberg et al., 2003). In fact, comorbidity of psychopathology is a highly general phenomenon in the psychiatric field and no diagnostic grouping seems to be safe from comorbidity of psychopathology (Krueger and Markon, 2006). The results of this study suggest that comorbidity issues need to be more thoroughly investigated when establishing a classification system for the neuropsychiatric symptoms of AD. In this study, the prevalence of neuropsychiatric symptoms and syndromes of AD were rather high. It is well known that prevalence estimates of neuropsychiatric symptoms in AD vary widely from 60% to 100% (Tariot et al., 1995; Mack et al., 1999; Lyketsos et al., 2000; Tatsch et al., 2006). In this study, several factors could have affected the results. The first is the characteristic of the instrument utilized neuropsychiatric assessment. The prevalence of neuropsychiatric symptoms of AD tend to be higher in the studies using the BRSD (Tariot et al., 1995; Mack et al., 1999; Youn et al., 2008) than in the studies using the neuropsychiatric inventory (NPI) (Lyketsos et al., 2000, 2002; Peters et al., 2006; Tatsch et al., 2006; Dechamps et al., 2008). The NPI is administered using brief screening questions, followed up by sub-questions if the response to the screening questions indicates problems. In contrast, all 45 items relating to specific neuropsychiatric symptoms need to be asked to the informant to complete the BRSD. This raises the possibilities that the neuropsychiatric symptoms detected by the sub-questions of the NPI might be missed by the screening question, indicating that no problems were present (Mack et al., 1999). Thus, it is possible that prevalence rate estimated by the BRSD tend to higher than that estimated by the NPI. The second potential factor is the characteristics of the study sample. It is probable that prevalence estimated from a clinic or an institution derived sample tend to be higher than those from a communitybased sample (Lyketsos et al., 2000, 2002; Peters et al., 2006; Tatsch et al., 2006; Dechamps et al., 2008). In this study, all subjects were recruited from dementia special clinics. The third factor is the definition of the presence of neuropsychatric symptoms could affect the results. In this study, neuropsychiatric symptoms were
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rated as present if symptoms were present for at least 3 days within the past month. The same or similar approaches have also been used to detect the clinically relevant symptoms in previous studies (Tractenberg et al., 2000; Aalten et al., 2007). The fourth is the medication effects. We did not strictly control the effect of medication. However, evaluation of most of the subjects was undertaken before any medication for behavioral control. In addition, previous studies reported little effect of antipsychotics and antidepressant on the frequency of neuropsychiatric symptoms (Aalten et al., 2007; Zuidema et al., 2007). In this study, the prevalence of neuropsychiatric symptoms or syndromes varied with the severity of AD. Numbers of comorbid neuropsychiatric symptoms and syndromes were also varied with the severity of AD. Most peak estimates were found after the moderate stages of AD. Similar inverted U shape patterns, illustrating the prevalence of neuropsychiatric symptoms of AD, were also found in many previous studies (Levy et al., 1996; Lopez et al., 2003; Tractenberg et al., 2003). These results could be interpreted to mean that number of neuropsychiatric symptoms of AD was increased with disease progression and then decreased with severe brain dysfunction. One interesting finding of this study is that about 85% of the patients with very mild AD (CDR 0.5) had one or more neuropsychiatric syndrome although their prevalence estimate was lower than that of other stages of AD. Because CDR 0.5 is a heterogenous group, it includes MCI and very mild AD (Petersen et al., 1999). Recent studies showed that prevalence estimates of neuropsychiatric symptoms ranged from 43% to 75% even with mild cognitive impairment (Lyketsos et al., 2002; Apostolova and Cummings, 2008). In this study, only very mild AD were included in the analysis and results of this study suggests that neuropsychiatric symptoms are valuable initial symptoms for those subjects who are developing AD. Results that depressive symptoms were most common in moderate stage were influenced by the analytic methods of this study. When very mild AD group was combined with the mild AD group as in other studies, the prevalence of depressive symptoms was not significantly different across the severities of AD. This result supported the results of previous studies (Lopez et al., 2003; Craig et al., 2005) although some studies have also found an association of mild severity of AD and depression (Chen et al., 2000). Although relationships among neuropsychiatric syndromes were not rigorously investigated, the results of this study were generally consistent with those of previous studies (Lopez et al., 2003; Tractenberg et al., 2003). Irritability/aggression which is comparable to agitation in other studies had significant associations with various neuropsychiatric syndromes including behavioral dysregulation, vegetative symptoms and depression (Lyketsos et al., 1999, 2001b). Association between depression and psychosis was reported although a lack of association has also reported in the literature (Bassiony and Lyketsos, 2003). Results of this study also indicated that some neuropsychiatric syndromes could predict the existence of other syndromes but the reverse was not always useful as a predictor. For example, psychosis could predict the existence of behavioral dysregulation but opposite was not true. This implied that behavioral dysregulation including wandering and sundowning symptoms, could not predict the occurrence of psychotic symptoms although the presence of psychotic symptoms elevated the risk of behavioral dysregulation. As for the relationship among the neuropsychiatric syndromes, it should be mentioned that changes in the interrelationship among the neuropsychiatric syndromes according to the severity of the disease could be possible even though we statistically control for the severity of the disease. For example, one large sample study reported that psychosis was associated with aggression in moderate to severe stage but with psychomotor agitation in mild stages (Lopez et al., 2003).
This study demonstrated that neuropsychiatric symptoms and syndromes were highly prevalent in AD. It also suggested that the multidimensional complexity of the neuropsychiatric syndromes of AD should be considered when researching these syndromes. Conflict of interest statement None. Acknowledgement This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea. (Grant No.: A070001, A090742). A part of this work was presented at the Controversies on Neurology in October 24–7, 2008. References Aalten, P., Verhey, F.R., Boziki, M., Bullock, R., Byrne, E.J., Camus, V., Caputo, M., Collins, D., De Deyn, P.P., Elina, K., Frisoni, G., Girtler, N., Holmes, C., Hurt, C., Marriott, A., Mecocci, P., Nobili, F., Ousset, P.J., Reynish, E., Salmon, E., Tsolaki, M., Vellas, B., Robert, P.H., 2007. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: Part I. Dement. Geriatr. Cogn. Disord. 24, 457–463. Apostolova, L.G., Cummings, J.L., 2008. Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature. Dement. Geriatr. Cogn. Disord. 25, 115–126. Bassiony, M.M., Lyketsos, C.G., 2003. Delusions and hallucinations in Alzheimer’s disease: review of the brain decade. Psychosomatics 44, 388–401. Chen, J.C., Borson, S., Scanlan, J.M., 2000. Stage-specific prevalence of behavioral symptoms in Alzheimer’s disease in a multi-ethnic community sample. Am. J. Geriatr. Psychiatry 8, 123–133. Craig, D., Mirakhur, A., Hart, D.J., Mcilroy, S.P., Passmore, A.P., 2005. A crosssectional study of neuropsychiatric symptoms in 435 patients with Alzheimer’s disease. Am. J. Geriatr. Psychiatry 13, 460–468. Dechamps, A., Jutand, M.A., Onifade, C., Richard-Harston, S., Bourdel-Marchasson, I., 2008. Co-occurrence of neuropsychiatric syndromes in demented and psychotic institutionalized elderly. Int. J. Geriatr. Psychiatry 23, 1182–1190. Dunkin, J.J., Anderson-Hanley, C., 1998. Dementia caregiver burden: a review of the literature and guidelines for assessment and intervention. Neurology 51, S53– S60 (discussion S65–S67). Harwood, D.G., Ownby, R.L., Barker, W.W., Duara, R., 1998. The factor structure of the Cornell Scale for depression in dementia among probable Alzheimer’s disease patients. Am. J. Geriatr. Psychiatry 6, 212–220. Hughes, C.P., Berg, L., Danziger, W.L., Coben, L.A., Martin, R.L., 1982. A new clinical scale for the staging of dementia. Br. J. Psychiatry 140, 566–572. Jeste, D.V., Wragg, R.E., Salmon, D.P., Harris, M.J., Thal, L.J., 1992. Cognitive deficits of patients with Alzheimer’s disease with and without delusions. Am. J. Psychiatry 149, 184–189. Krueger, R.F., Markon, K.E., 2006. Reinterpreting comorbidity: a model-based approach to understanding and classifying psychopathology. Annu. Rev. Clin. Psychol. 2, 111–133. Lee, J.H., Lee, K.U., Lee, D.Y., Kim, K.W., Jhoo, J.H., Kim, J.H., Lee, K.H., Kim, S.Y., Han, S.H., Woo, J.I., 2002. Development of the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries. J. Gerontol. B: Psychol. Sci. Soc. Sci. 57, P47–P53. Levy, M.L., Miller, B.L., Cummings, J.L., Fairbanks, L.A., Craig, A., 1996. Alzheimer disease and frontotemporal dementias. Behavioral distinctions. Arch. Neurol. 53, 687–690. Lopez, O.L., Becker, J.T., Sweet, R.A., Klunk, W., Kaufer, D.I., Saxton, J., Habeych, M., Dekosky, S.T., 2003. Psychiatric symptoms vary with the severity of dementia in probable Alzheimer’s disease. J. Neuropsychiatry Clin. Neurosci. 15, 346–353. Lyketsos, C.G., Steele, C., Galik, E., Rosenblatt, A., Steinberg, M., Warren, A., Sheppard, J.M., 1999. Physical aggression in dementia patients and its relationship to depression. Am. J. Psychiatry 156, 66–71. Lyketsos, C.G., Steinberg, M., Tschanz, J.T., Norton, M.C., Steffens, D.C., Breitner, J.C., 2000. Mental and behavioral disturbances in dementia: findings from the Cache County Study on memory in aging. Am. J. Psychiatry 157, 708–714. Lyketsos, C.G., Breitner, J.C., Rabins, P.V., 2001a. An evidence-based proposal for the classification of neuropsychiatric disturbance in Alzheimer’s disease. Int. J. Geriatr. Psychiatry 16, 1037–1042. Lyketsos, C.G., Sheppard, J.M., Steinberg, M., Tschanz, J.A., Norton, M.C., Steffens, D.C., Breitner, J.C., 2001b. Neuropsychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache County Study. Int. J. Geriatr. Psychiatry 16, 1043–1053. Lyketsos, C.G., Lopez, O., Jones, B., Fitzpatrick, A.L., Breitner, J., Dekosky, S., 2002. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
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Archives of Gerontology and Geriatrics journal homepage: www.elsevier.com/locate/archger
Prevalence of neuropsychiatric syndromes in Alzheimer’s disease (AD) Jong Chul Youn a, Dong Young Lee b, Jin Hyeong Jhoo c, Ki Woong Kim d, Il Han Choo b, Jong Inn Woo b,* a
Department of Neuropsychiatry, Kyunggi Provincial Hospital for the Elderly, Yongin, Kyunggi-do 449-769, Republic of Korea Department of Neuropsychiatry, Seoul National University College of Medicine and Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea c Department of Neuropsychiatry, Kangwon National University College of Medicine and Kangwon National University Hospital, Chuncheon, 200-722 Kangwon-do, Republic of Korea d Department of Neuropsychiatry, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Sungnam, Kyunggi-do 463-707, Republic of Korea b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 April 2009 Received in revised form 18 April 2010 Accepted 19 April 2010 Available online 26 May 2010
This study aimed to estimate the prevalence and explore the multidimensional complexity of the neuropsychiatric syndromes of AD. Neuropsychiatric symptoms and syndromes of 216 subjects with probable and possible AD diagnosed by NINCDS-ADRDA criteria were evaluated by the Korean version of behavior rating scale for dementia (BRSD-K). The prevalence rate of six neuropsychiatric syndromes (depressive symptoms, inertia, vegetative symptoms, irritability/aggression, behavioral dysregulation, psychotic symptoms) and comorbid neuropsychiatric syndromes were calculated according to the Clinical Dementia Rating scale. To investigate the relationship among neuropsychiatric syndromes, logistic regression analyses were performed. About 95% of patients with AD had one or more neuropsychiatric symptoms and syndromes during the past month. Among the neuropsychiatric syndromes, irritability/aggression (76.2%) was the most frequent, followed by apathy (72.3%) and depressive symptoms (68.0%). About 90% of the subjects had one or more comorbid neuropsychiatric syndromes. The mean numbers of comorbid neuropsychiatric syndromes were significantly varied according to the severity of disease (p < 0.05). Depressive symptoms were significantly associated with vegetative symptoms and irritability/aggression (p < 0.05). Inertia and psychotic symptoms were significantly associated with vegetative symptoms and behavioral dysregulation, respectively (p < 0.05). This study demonstrated that neuropsychiatric syndromes of AD were highly prevalent and involved complex relationships among them. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Alzheimer’s disease Neuropsychiatric symptom Neuropsychiatric syndrome Comorbidity Behavior rating scale for dementia
1. Introduction Neuropsychiatric symptoms should be regarded as one of the central symptoms of AD. They have been associated with a greater degree of cognitive impairment (Jeste et al., 1992; Perez-Madrinan et al., 2004), rapid disease progression (Mortimer et al., 1992; Stern et al., 1997), caregiver burden (Rabins et al., 1982; Dunkin and Anderson-Hanley, 1998) and early institutionalization (Steele et al., 1990; O’Donnell et al., 1992). Neuropsychiatric symptoms of AD are not a unitary concept (Robert et al., 2005). They include a very wide range of individual symptoms. The prevalence estimates of these varied, from 60% to 90%, mainly as a result of differences in the evaluation method and clinical characteristics of the study sample (Mack et al., 1999; Lyketsos et al., 2002; McKeith and Cummings, 2005). Because neuropsychiatric symptoms of AD were closely linked
* Corresponding author. Tel.: +82 2 2072 2456; fax: +82 2 2072 3176. E-mail address: [email protected] (J.I. Woo). 0167-4943/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2010.04.015
with one or more other symptoms, a syndromatic approach which conceptualized the neuropsychiatric symptoms of AD as constellations of several syndromes like depression, psychosis and agitation (Harwood et al., 1998; Mack et al., 1999; Aalten et al., 2007) has an advantage in identifying the biological correlates and estimating the treatment response (Robert et al., 2005; Aalten et al., 2007). Based on the results of studies using this approach, several others proposed a classification system of neuropsychiatric symptoms of AD (Lyketsos et al., 2001a,b; Robert et al., 2005). However, several issues regarding neuropsychiatric syndromes of AD should be further investigated. For example, the prevalence of neuropsychiatric syndromes of AD has been rarely investigated (Aalten et al., 2007). In spite of the evidence that neuropsychiatric syndromes of AD are not likely to appear alone and most likely to occur with other syndromes (Dechamps et al., 2008), interrelationships among the neuropsychiatric syndromes of AD have rarely been examined. Thus, this study aimed to estimate the prevalence and explore the multidimensional complexity of the neuropsychiatric syndromes of AD.
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2. Subjects and methods
Table 1 Demographic and clinical characteristics of study subjects.
2.1. Subjects Two hundred sixteen subjects with probable and possible AD, according to the NINCDS-ADRDA criteria (McKhann et al., 1984), were enrolled from two special dementia clinics: the Seoul National University Hospital and Kyunggi Provincial Hospital for the Elderly. Most subjects were community dwellers at the time of behavioral evaluation. On entry into the study, informed consent was obtained from patients or their family caregivers according to the guidelines issued by the institutional review boards of the hospitals involved. All participants were evaluated in accordance with the clinical assessment protocol of the Korean version of CERAD (CERAD-K) (Lee et al., 2002). Severity of dementia was evaluated using the clinical dementia rating (CDR) scale (Hughes et al., 1982). Final diagnosis and severity were assigned by a consensus panel comprised of at least four geriatric psychiatrists with expertise in dementia research after reviewing the available neuropsychological test results and neuroimaging data. Although medications were not controlled during this study, most of the subjects were evaluated before taking any medication to reduce BPSD. Subjects without a reliable informant were excluded from the study. 2.2. Behavioral assessment Neuropsychiatric symptoms and syndromes were evaluated by the Korean version of the behavior rating scale for dementia (BRSDK) which consists of 46 questions related to the neuropsychiatric symptoms of AD (Tariot et al., 1995; Youn et al., 2008). Thirty-eight items of the 46 items were scaled by frequency with possible ratings as follows: 0 = not occurred since illness began; 1 = present 1–2 days in the past month; 2 = present 3–8 days in the past month; 3 = present 9–15 days in the past month; 4 = present 16 days or more in the past month; 8 = occurred since illness began but not in during the past month; 9 = unable to rate. To calculate the prevalence of clinically relevant neuropsychiatric symptoms, a symptom was recorded as present if symptoms were present at least 3 days within the past month. The remaining eight items (items 9, 10, 12, 14, 5, 17, 26, 32) were framed relative to ‘‘before dementia began’’ and were rated as present or absent. The presence of six neuropsychiatric syndromes (depressive symptoms, inertia, vegetative symptoms, irritability/aggression, behavioral dysregulation, psychotic symptoms), which were included as subscales in BRSD-K, were rated as being present when any items in the subscales were rated as present in the previous month. The BRSD-K was administered within 3 months of a CERAD evaluation for each subject. 2.3. Statistical analysis Frequencies of neuropsychiatric symptoms and syndromes of AD, according to the severity of disease, were calculated. Frequencies of comorbid neuropsychiatric symptoms and syndromes were also calculated. To evaluate the likelihood that subjects exhibiting one neuropsychiatric syndrome would also exhibit another neuropsychiatric syndrome, forward logistic regression analyses using age, sex, education, APOE genotype and CDR score as independent variable were performed. All statistical analyses were performed by SPSS 11.0. 3. Results 3.1. Demographic and clinical characteristics of the subjects The age of the subjects ranged from 48 to 98 years, with a mean age of 72.9 9.9 years. About 70% of the subjects were female. While
259
Number
Mean S.D.
Age (years) Female Education (years)
216 216 216
72.9 9.9
Diagnosis Probable AD Possible AD
216
CDR 0.5 1 2 3
216
Duration of illness (years) MMSE Blessed ADL
205 172 216
n (%) 150 (69.4)
6.3 5.7 144 (66.7) 72 (33.3)
30 90 61 35
(13.9) (41.7) (28.2) (16.2)
4.1 2.5 14.4 6.0 6.0 3.9
mean education years was relatively low (6.3 5.7), there was a broad range in years of school completed (0–20). Diagnosis of probable AD was 66.7%. More than half of subjects had dementia below the mild level of severity. Thirty subjects had CDR 0.5; 90 subjects, CDR 1; 61 subjects, CDR 2; 35 subjects, CDR 3. A total 172 subjects completed the MMSE and the mean score was 14.4 2.5. Most of the informants lived with the study subjects (81%) and were the spouse (37.5%) or children (33.8%) of the subjects (Table 1). 3.2. Prevalence of neuropsychiatric symptoms and syndrome Nearly all (96.3%) of the subjects had one or more neuropsychiatric symptom during the past month. The frequencies of neuropsychiatric symptoms ranged from 1.9% (item 35, misidentification of objects; item 39, belief that the caregiver is an imposter) to 70.4% (item 30, verbal repetitiveness) (Table 2). Neuropsychiatric symptoms of AD with the highest frequencies were, in decreasing order, verbal repetitiveness (70.4%), loss of enjoyment (51.9%), irritability (44.9%), loss of initiative (41.2%) and tiredness (36.1%). In line with neuropsychiatric symptoms, 94.4% subjects had one or more neuropsychiatric syndromes. Inertia (70.4%) was the most frequent, followed by irritability/aggression (67.3%), depressive symptoms (54.2%), behavioral dysregulations (51.4%) and psychotic symptoms (25.0%) (Table 3). Frequencies of neuropsychiatric symptoms and syndromes were varied according to the severity of disease. Among 45 items, frequencies of 20 neuropsychiatric symptoms were significantly different with respect to the severity of AD (p < 0.05). Frequencies of most neuropsychiatric symptoms peaked in moderate to severe stages of AD other than two symptoms (item 9, loss of enjoyment; item 31, social withdrawal) both of which had their highest frequencies in mild level of disease severity. Frequencies of all neuropsychiatric syndromes except vegetative symptom were significantly different in relation to the severity of disease (p < 0.05) and the highest was observed in moderate to severe stages. Inertia showed the highest frequency in mild stages. 3.3. Comorbid neuropsychiatric symptoms and syndromes Most of the study subjects (92.1%) had two or more neuropsychiatric symptoms and the mean number of neuropsychiatric symptoms per individual was 9.0 6.6. A large percentage of the subjects (85.5%) also had one or more comorbid neuropsychiatric syndrome with a mean number of comorbid syndrome per individual of 3.1 1.7. The mean number of comorbid neuropsychiatric symptoms and syndromes also varied significantly according to the severity of disease (F = 6.72, df = 3, p = 0.001 for neuropsychiatric symptom; F = 8.64, df = 3, p = 0.001 for neuropsychiatric syndrome).
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Table 2 Prevalence of individual neuropsychiatric symptoms in AD. Item 1. Feeling of anxiety 2. Physical sign of anxiety 3. Sad appearance 4. Feeling of hopelessness 5. Crying 6. Felling of guilt 7. Poor self-esteem 8. Wish to die 9. Loss of enjoyment 10. Loss of initiative 11. Tiredness 12. Altered sleep pattern 13.Trouble in sleeping 14. Change in appetite 15. Change in weight 16.Excessive complaints 17. Change in sexual drive 18. Sudden changes in emotion 19. Agitation 20. Irritability 21. Uncooperativeness 22. Verbal aggression 23. Physical aggression 24. Restlessness 25. Purposeless behavior 26. Diurnal pattern of confusion 27. Purposeless wandering 28. Attempts to leave resid. 29. Socially inappropriate behavior 30. Verbal repetitiveness 31. Social withdrawal 32. Attention seeking 33. Misidentific. of people 34. Misidentific. of self 35. Misidentific. of objects 36. Belief: is being hared 37. Belief: spouse unfaithful 38. Belief: being abandoned 39. Belief: caregiver imposter 40. Belief: TV characters are real 41. Belief: people in house 42. Belief: deads alive 43. Belief: house is not home 44. Auditory hallucination 45. Visual hallucination
Total 26.4 30.6 35.6 21.3 21.3 5.6 12.0 12.0 51.9 41.2 36.1 30.1 19.9 20.8 14.8 17.1 6.9 6.9 23.6 44.9 36.6 20.4 8.3 27.8 36.1 18.1 15.7 11.1 13.4 70.4 31.5 34.3 10.2 3.7 1.9 21.3 4.2 5.1 1.9 7.9 8.3 7.9 11.6 7.4 6.5
CDR0.5
CDR1
16.7 20.0 30.0 13.3 23.3 3.3 10.0 6.7 16.7 26.7 23.3 20.0 13.3 20.0 3.3 6.7 3.3 10.0 6.7 26.7 16.7 6.7 0 6.7 20.0 6.7 3.3 0 3.3 66.7 66.7 13.3 0 0 0 13.3 0 0 3.3 0 0 0 0 0 0
CDR2
26.7 36.7 40.0 28.9 15.6 3.3 17.8 13.3 66.7 47.8 40.0 28.9 18.9 16.7 20.0 22.2 4.4 4.4 23.3 46.7 37.8 18.9 5.6 24.4 28.9 10.0 10.0 6.7 11.1 77.8 77.8 32.2 6.7 0 1.1 26.7 5.6 4.4 2.2 2.2 5.6 4.4 5.6 4.4 5.6
The mean number of comorbid neuropsychiatric symptoms was 4.7 4.8 in CDR 0.5, 8.98 6.1 in CDR 1, 11.09 6.77 in CDR 2, 9.11 6.6 in CDR 3 (Fig. 1A). The mean number of comorbid neuropsychiatric syndromes was 1.8 1.5 in CDR 0.5, 3.1 1.6 in CDR 1, 3.6 1.6 in CDR 2, 3.3 1.8 in CDR 3 (Fig. 1B). Results of Turkey-b post hoc test shows that subjects with CDR 0.5 had a smaller number of comorbid neuropsychiatric symptoms and syndromes than subjects with other stages.
37.7 31.1 36.1 19.7 29.5 9.8 11.5 13.1 55.7 42.6 36.1 34.4 18.0 24.6 8.2 16.4 13.1 3.3 37.7 52.5 44.3 27.9 14.8 34.4 49.2 32.8 24.6 16.4 23.0 78.7 78.7 52.5 16.4 6.6 1.6 21.3 6.6 11.5 0 14.8 13.1 13.1 21.3 9.8 6.6
CDR3
p < 0.05
14.3 22.9 28.6 11.4 20.0 5.7 0 11.4 37.1 34.3 37.1 34.3 31.4 25.7 22.9 14.3 5.7 17.1 14.3 42.9 37.1 22.9 11.4 42.9 45.7 22.9 25.7 22.9 11.4 40.0 40.0 25.7 17.1 11.4 5.7 14.3 0 0 2.9 17.1 14.3 14.3 20.0 17.1 14.3
*
*
* *
* * * * * * * * * *
*
*
* * * *
3.4. Relationships among neuropsychiatric syndromes The relationships among the neuropsychiatric syndromes evaluated by regression analysis were presented in Table 4. Irritability/aggression is associated with depression, vegetative symptoms and behavioral dysregulation. Psychosis was associated with depression and behavioral dysregulation. Among the clinical and demographic variables, education was associated with apathy
Table 3 Prevalence of neuropsychiatric syndromes of Alzheimer’s disease, n (%). Total
Number Depressive symptoms Inertia Vegetative symptoms Irritability/aggression Behavioral dysregulation Psychotic symptoms No neuropsychiatric syndrome
117 152 101 140 111 54 12
(54.2) (70.4) (46.8) (67.3) (51.4) (25.0) (5.6)
Severity CDR 0.5
CDR 1
CDR 2
CDR3
30 14 12 9 13 7 0 5
90 52 74 43 60 35 14 4
61 37 42 32 45 43 25 2
35 14 24 17 22 26 15 1
(46.7) (40.0) (30.0) (43.3) (23.3) (16.7)
(57.8) (82.2) (47.8) (66.7) (38.9) (15.6) (4.4)
(60.7) (68.9) (52.5) (73.8) (70.5) (41.0) (3.3)
Notes: all items show a significance of p < 0.05 by x2 analysis (except the vegetative symptoms) according to the severity of dementia.
(40.0) (68.6) (48.6) (62.9) (74.3) (42.9) (2.9)
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Fig. 1. Frequencies of comorbid neuropsychiatric symptoms (A) and syndromes (B) according to severity of Alzheimer’s disease.
and behavioral dysregulation and CDR score was associated with psychotic symptoms. 4. Discussion This study demonstrated that neuropsychiatric symptoms and syndromes of AD were highly prevalent and inter-correlated. In this study, about 90% of AD patients had comorbid neuropsychiatric symptoms. Because neuropsychiatric symptoms are inter-correlated (Lyketsos et al., 2002), several studies have attempted to classify the neuropsychiatric symptoms of AD into 3–6 neuropsychiatric syndromes, both statistically and conceptually (Lyketsos et al., 2001a,b; Aalten et al., 2007). Although this syndromatic approach could help to identify the subgroups of AD patients with different symptom complexes which might reflect a different prevalence, progression, biological correlates and treatment response (Lyketsos et al., 2001a,b), the results of this study showed that individual neuropsychiatric syndromes of AD were not independent from each other. In this Table 4 Relationships among the neurobehavioral syndromes of AD.a.
b
OR (95%CI)
p<
Depressive symptoms Irritability Psychotic symptoms
0.83 1.14
2.29 (1.18–4.47) 3.14 (1.40–7.01)
0.015 0.005
Inertia Education Vegetative symptoms
0.07 1.63
1.07 (1.02–1.14) 5.08 (2.31–11.12)
0.044 0.0001
Vegetative symptoms Inertia Psychotic symptoms Irritability
1.31 0.84 0.87
3.71 (1.69–8.17) 2.32 (1.06–5.09) 2.39 (1.18–4.87)
0.001 0.036 0.016
Irritability/aggression Depressive symptoms Vegetative symptom Dysregulation
0.86 0.910 1.73
2.36 (1.15–4.85) 2.48 (1.19–5.19) 5.65 (2.62–12.16)
0.019 0.015 0.001
Behavioral dysregulation Irritability Psychotic symptoms Education
1.89 2.53 0.07
6.58 (2.85–15.2) 12.55 (4.00–39.3) 0.93 (0.87–0.99)
0.001 0.001 0.032
Psychotic symptoms CDR rating Depressive symptoms Behavioral dysregulation
1.37 1.57 2.44
3.94 (2.04–7.62) 4.79 (1.77–12.96) 11.48 (3.61–36.46)
0.001 0.002 0.001
a
Age, sex, education, APOE and CDR rating were used as independent variables.
study, about 85% of AD subjects had two or more neuropsychiatric syndromes. This result was consistent with the results of previous studies focused to the overlapping among the neuropsychiatric syndromes of AD (Tractenberg et al., 2003; Dechamps et al., 2008). One nursing home study for 109 subjects with dementia reported that about 85% of the dementia subjects had one or more neuropsychiatric syndrome (Dechamps et al., 2008). In the other community study, which targeted three neuropsychiatric syndrome, 82% of subjects with AD had two or more neuropsychiatric syndromes (Tractenberg et al., 2003). In fact, comorbidity of psychopathology is a highly general phenomenon in the psychiatric field and no diagnostic grouping seems to be safe from comorbidity of psychopathology (Krueger and Markon, 2006). The results of this study suggest that comorbidity issues need to be more thoroughly investigated when establishing a classification system for the neuropsychiatric symptoms of AD. In this study, the prevalence of neuropsychiatric symptoms and syndromes of AD were rather high. It is well known that prevalence estimates of neuropsychiatric symptoms in AD vary widely from 60% to 100% (Tariot et al., 1995; Mack et al., 1999; Lyketsos et al., 2000; Tatsch et al., 2006). In this study, several factors could have affected the results. The first is the characteristic of the instrument utilized neuropsychiatric assessment. The prevalence of neuropsychiatric symptoms of AD tend to be higher in the studies using the BRSD (Tariot et al., 1995; Mack et al., 1999; Youn et al., 2008) than in the studies using the neuropsychiatric inventory (NPI) (Lyketsos et al., 2000, 2002; Peters et al., 2006; Tatsch et al., 2006; Dechamps et al., 2008). The NPI is administered using brief screening questions, followed up by sub-questions if the response to the screening questions indicates problems. In contrast, all 45 items relating to specific neuropsychiatric symptoms need to be asked to the informant to complete the BRSD. This raises the possibilities that the neuropsychiatric symptoms detected by the sub-questions of the NPI might be missed by the screening question, indicating that no problems were present (Mack et al., 1999). Thus, it is possible that prevalence rate estimated by the BRSD tend to higher than that estimated by the NPI. The second potential factor is the characteristics of the study sample. It is probable that prevalence estimated from a clinic or an institution derived sample tend to be higher than those from a communitybased sample (Lyketsos et al., 2000, 2002; Peters et al., 2006; Tatsch et al., 2006; Dechamps et al., 2008). In this study, all subjects were recruited from dementia special clinics. The third factor is the definition of the presence of neuropsychatric symptoms could affect the results. In this study, neuropsychiatric symptoms were
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rated as present if symptoms were present for at least 3 days within the past month. The same or similar approaches have also been used to detect the clinically relevant symptoms in previous studies (Tractenberg et al., 2000; Aalten et al., 2007). The fourth is the medication effects. We did not strictly control the effect of medication. However, evaluation of most of the subjects was undertaken before any medication for behavioral control. In addition, previous studies reported little effect of antipsychotics and antidepressant on the frequency of neuropsychiatric symptoms (Aalten et al., 2007; Zuidema et al., 2007). In this study, the prevalence of neuropsychiatric symptoms or syndromes varied with the severity of AD. Numbers of comorbid neuropsychiatric symptoms and syndromes were also varied with the severity of AD. Most peak estimates were found after the moderate stages of AD. Similar inverted U shape patterns, illustrating the prevalence of neuropsychiatric symptoms of AD, were also found in many previous studies (Levy et al., 1996; Lopez et al., 2003; Tractenberg et al., 2003). These results could be interpreted to mean that number of neuropsychiatric symptoms of AD was increased with disease progression and then decreased with severe brain dysfunction. One interesting finding of this study is that about 85% of the patients with very mild AD (CDR 0.5) had one or more neuropsychiatric syndrome although their prevalence estimate was lower than that of other stages of AD. Because CDR 0.5 is a heterogenous group, it includes MCI and very mild AD (Petersen et al., 1999). Recent studies showed that prevalence estimates of neuropsychiatric symptoms ranged from 43% to 75% even with mild cognitive impairment (Lyketsos et al., 2002; Apostolova and Cummings, 2008). In this study, only very mild AD were included in the analysis and results of this study suggests that neuropsychiatric symptoms are valuable initial symptoms for those subjects who are developing AD. Results that depressive symptoms were most common in moderate stage were influenced by the analytic methods of this study. When very mild AD group was combined with the mild AD group as in other studies, the prevalence of depressive symptoms was not significantly different across the severities of AD. This result supported the results of previous studies (Lopez et al., 2003; Craig et al., 2005) although some studies have also found an association of mild severity of AD and depression (Chen et al., 2000). Although relationships among neuropsychiatric syndromes were not rigorously investigated, the results of this study were generally consistent with those of previous studies (Lopez et al., 2003; Tractenberg et al., 2003). Irritability/aggression which is comparable to agitation in other studies had significant associations with various neuropsychiatric syndromes including behavioral dysregulation, vegetative symptoms and depression (Lyketsos et al., 1999, 2001b). Association between depression and psychosis was reported although a lack of association has also reported in the literature (Bassiony and Lyketsos, 2003). Results of this study also indicated that some neuropsychiatric syndromes could predict the existence of other syndromes but the reverse was not always useful as a predictor. For example, psychosis could predict the existence of behavioral dysregulation but opposite was not true. This implied that behavioral dysregulation including wandering and sundowning symptoms, could not predict the occurrence of psychotic symptoms although the presence of psychotic symptoms elevated the risk of behavioral dysregulation. As for the relationship among the neuropsychiatric syndromes, it should be mentioned that changes in the interrelationship among the neuropsychiatric syndromes according to the severity of the disease could be possible even though we statistically control for the severity of the disease. For example, one large sample study reported that psychosis was associated with aggression in moderate to severe stage but with psychomotor agitation in mild stages (Lopez et al., 2003).
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