International Journal of Neuroscience, 2014; 124(7): 512–517 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2013.856902
RESEARCH ARTICLE
Vascular factors are associated with the severity of the neuropsychiatric symptoms in Alzheimer’s disease Yeonsil Moon,1 Heejin Kim,1 Jin Ok Kim,1 and Seol-Heui Han1,2 1
Department of Neurology, Konkuk University Medical Center, Seoul, Republic of Korea; 2 Center for Geriatric Neuroscience Research, Institute of Biomedical Science, Konkuk Medical Science Research Center, Konkuk University, Seoul, Republic of Korea Introduction: The purpose of this study is to determine whether vascular risk factors are associated with severity of neuropsychiatric symptoms (NPS) in patients of Alzheimer’s dementia. Methods: We reviewed medical records of 162 patients with Alzheimer’s dementia. The NPS were assessed using the Neuropsychiatric Inventory (NPI). Hypertension and cardiovascular events were detected through detailed history taking. Diabetes mellitus and hyperlipidemia were uncovered through laboratory test. The asymptomatic stroke and white matter hyperintensities (WMH) were defined by magnetic resonance imaging. Partial correlation analysis was used. Results: Hypertension was correlated with the severity of apathy (r = 0.231, p = 0.015). The asymptomatic stroke was related to the severity of depression (r = 0.255, p = 0.007). The remaining vascular factors were not significant. Conclusion: Presence of hypertension and asymptomatic stroke are related with the severity of apathy and depression in Alzheimer’s dementia. KEYWORDS: hypertension, asymptomatic stroke, apathy, depression
Introduction Dementia is a syndrome with cognitive decline and behaviour problems that lead to impairments in activities of daily living (ADL). Although cognitive impairment is the most important problem that compromises ADL, neuropsychiatric symptoms (NPS) also have practical effects on the quality of life [1–3]. The NPS are risk factors which lead the Alzheimer’s disease (AD) patients to impairment in instrumental ADL more rapidly, and increase the mortality of AD patients [4,5]. The NPS are poorly correlated with cognitive decline and respond to medication unsatisfactorily. While cognitive decline is associated with atrophy of hippocampus and posterior association cortex [6], NPS are associated with diverse structures except hippocampus [7–9]. This dissociation suggests that risk factors contributing to NPS might be different from those of cognitive decline.
Received 18 July 2013; revised 14 October 2013; accepted 14 October 2013 Correspondence: Seol-Heui Han, Department of Neurology, 143–729, Konkuk University Medical Center, 120–1 Neungdong-ro (Hwayang-dong), Gwangjin-gu, Seoul, Republic of Korea. Tel: +82–2–2030–7460. Fax: +82–2–2030–7469 E-mail: [email protected]
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Many risk factors contributing to NPS has been revealed. Depression, apathy, agitation, aggression and psychosis, are confirmed as significant consequences of aging [10–12]. Less education is associated with increased rates of depression, agitation and aggression [13]. The E4 allele of the Apolipoprotein E (ApoE) is one of the noted risk factors for NPS in AD patients. Some studies report that agitation, aggression, depression and psychosis (such as delusions and hallucinations) are more common in patients with the ApoE e4 allele [14,15]. Vascular factors also contribute to the development of NPS. Stroke prior to the onset of AD and hypertension increase the risk of delusion, depression, apathy, anxiety and aggression [16]. The white mater hyperintensities (WMH) in patients with dementia are associated with a dysexecutive-related behavioural symptom in AD [17]. These vascular risk factors that increase NPS are critical because they are modifiable. However, little is known about the relationship between vascular risk factors and the NPS of AD, especially with severity of symptoms. The aim of this study is to determine whether vascular risk factors – including hypertension, diabetes mellitus, hyperlipidemia, cardiovascular events, WMH and asymptomatic stroke (AS) – are associated with severity of NPS in AD.
Vascular factors and neuropsychiatric symptoms
Methods Subjects We retrospectively reviewed medical records of patients with dementia from the Konkuk dementia registry. The Konkuk dementia registry is pooled data from patients who visited the memory clinic for cognitive and behavioural disturbances between March 2006 and October 2010. The data includes all available information such as basic demographic characteristics, other medical conditions, results of laboratory tests, global cognitive assessment, ApoE genotyping and brain imaging. Basic demographic characteristics include age, sex and years of education. Laboratory tests include complete blood count, electrolytes, total, High-density lipoprotein (HDL) and Low-density lipoprotein (LDL) cholesterol, triglyceride, free T4, T3, Thyroid-stimulating hormone, Human Immunodeficiency Virus, Venereal Disease Research Laboratory (VDRL), vitamin B12, folate and homocysteine levels. Comprehensive neuropsychological assessments were also included, which consisted of the modified Korean version of the Hopkins Verbal Learning Test for verbal memory, the Digit Span Forward and Backward for attention and working memory, the Rey-Osterrieth Complex Figure Test for nonverbal, visuospatial memory, the Korean version of the Boston Naming Test for language, the Stroop Test and the Word Fluency Test for frontal lobe function and the Rey-Osterrieth Complex Figure copy test for visuospatial function. ApoE genotyping was done after consent of the patients or carers, and brain imaging was acquired using brain magnetic resonance image (MRI). All data were collected during the second visit, which was within 1 to 2 months of the first visit. All the patients provided written informed consent to use their clinical data for research purposes, and this study was approved by the Institutional Review Boards of the Konkuk University Hospital.
Assessment of dementia Clinical diagnosis of dementia was assigned after review of all accessible information at consensus conferences that were attended by experienced neurologists and neuropsychologists. The diagnosis of AD followed National Institute of Neurological and Communicative Disorders and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria [18]. Only patients with a clinical diagnosis of ‘Probable AD’ were selected for the study. Patients with other dementia, or with mixed or atypical AD were excluded. AS which is not responsible for cognitive decline was not excluded from AD according to the criteria of the NINCDS-ADRDA. C
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Assessment of neuropsychiatric symptoms The NPS were assessed using the Neuropsychiatric Inventory (NPI). The NPI is a retrospective structured informant based rating scale used for patients with dementia [19]. The carer of the dementia patient scores each of 12 NPS; delusions, hallucinations, agitation, depression, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behaviour, night-time behaviour disturbances and appetite and eating abnormalities. The severity and frequency of each symptom are rated, and the descriptive score is obtained by multiplying severity by frequency. As the NPS were assessed at the second visit and the patients who are taking psychiatric drugs were not included in the registry, we could suppose that the concomitant pharmacological effect was excluded.
Definition of vascular risk factors and covariate Hypertension and diabetes mellitus were based on selfreport and medical record. Cardiovascular conditions that preceded the onset of dementia were ascertained through direct questions for heart attack, coronary artery bypass graft or stent insertion. Hyperlipidemia was diagnosed using the cut-off points of serum total cholesterol, HDL and LDL estimated through the laboratory test [20]. The AS was defined by MRI. MR images were obtained at the Konkuk University Medical Center using 3.0 Tesla unit (Signa HDx; GE Healthcare, Milwaukee, Wis) with an 8-channel high-resolution head coil. The axial and sagittal T1-weighted inversion-recovery [TR/TE/TI, 2468/12/920 ms; section thickness, 5 mm; matrix, 512 × 224); 2] axial T2-weighted fast spinecho (TR/effective TE, 4000/106 ms; section thickness, 5 mm; matrix 384 × 384); 3), axial fluid-attenuated inversion-recovery (TR/TE/TI, 11,000/105/2600 ms; section thickness, 5 mm; matrix, 384 × 224); 4) images of MRI was used for this study. The AS was defined as a focal hyperintense lesion on T2-weighted axial images and FLAIR of the patient who do not have corresponding symptoms in past history. The modified criteria of Fazekas et al. [21] or Scheltens et al. [22] was applied for evaluating the severity of WMH semiquantitatively, which is proposed by the Clinical Research for Dementia Of South Korea (CREDOS). The way to apply the scale is described in elsewhere, and the scale is confirmed through the high inter-rater and intra-rater reliabilities [23]. Dementia severity was interpreted using a global Clinical Dementia Rating (CDR) Score, which ranged from 0 to 3 [24].
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Statistical analysis Statistical analysis was done with SPSS version 17.0. Partial correlation analysis was used to predict the relationship of the NPS and the vascular risk factors. Age, educational level, presence of the ApoE e4 allele, severity of dementia (CDR score) and the other NPS except the target NPS were selected as covariates. These covariates are factors suggested to have effects on NPS based on previous reports. The p values of less than 0.05 were considered to indicate statistically significant differences.
Results Of the 579 data from the Konkuk dementia registry, 173 patients were diagnosed as “Probable AD”. Eleven patients were excluded because of incomplete data of the 173. Finally, data of the remaining 162 patients with probable AD were used for this study. (Figure 1) The general baseline characteristics of the patients for this study are detailed in Table 1. Female subjects were dominant, and the mean age was 74.06. The mean number of years of education was relatively low, 6.93 years. The range of CDR scores was 0.0 to 3.0, and most of the patients were in the very mild stage (CDR 0.5, 61.1%; CDR 1, 26.5%). More than half of the patients reported hypertension (59.3%), and 20.4% presented with diabetes mellitus. Cardiovascular events and hyperlipidemia were less common (13.6%, 15.4%). 8.6% of the patients had AS, and 62.3% of the patients revealed minimal WMH. About 60% of the patients had the ApoE e4 allele. Almost all patients reported at least one NPS (92%), and the severity of the NPS was relatively moderate (range of the total NPI was 0 to 75, Table 2). Apathy was the most common NPS (67.3%), and irritability and depression were also prevalent (48.8% and 46.3%, respectively). Elation and hallucination were the most uncommon symptoms, each presenting in 11 patients (6.8%). Age, educational level, presence of the ApoE e4 allele, and severity of dementia and WMH were correlated with scores of NPI. After adjusting for these factors, some vascular factors were associated with scores of NPI. Hypertension was correlated with the severity of apathy (r = 0.231, p = 0.015). The AS were related to the severity of depression (r = 0.255, p = 0.007) (Table 3). The remaining vascular factors (diabetes mellitus, hyperlipidemia, cardiovascular events and WMH) were not significant.
Discussion Hypertension breaks the blood–brain barrier and weakens the cerebral microcirculation. The impaired autoregulation leads the hemodynamic reserve to be reduced, which is a common cause of the decreased cerebral perfusion [25]. Hypoperfusion and the abnormal lesions that involve the posterior limb of the internal capsule [26], subcortical areas [27] and bilateral basal ganglia [28] are associated with apathy. These lesions are all on the path of the frontal-subcortical system from basal ganglia to frontal cortex, and damage of the frontalsubcortical system results in dopaminergic dysfunction. In AD, dopamine transporter uptake in the putamen is correlated with apathy [29]. The AS was the strongest factor that aggravated the depression. Lacunar infarctions or microbleeds in thalamus, basal ganglia and deep white matter are significantly associated with poststroke depression. Even though we did not systemically classify the locations of AS, almost all AS were lacunar infarctions in bilateral basal ganglia and thalamus which show no identifiable symptom. Disruption of the chemical neuroanatomy related to the frontal/temporal lobe-basal ganglia-ventral brainstem circuitry could result in dysfunction of the serotonergic systems, which are crucial components of mood [30,31]. In the present study, other vascular factors (diabetes mellitus, cardiovascular events) were not significantly associated with any NPS. This is similar with previous results which showed that diabetes mellitus, hyperlipidemia and cardiovascular events are not associated with the prevalence of any NPS; otherwise, hypertension and stroke were linked to agitation, anxiety, delusion, apathy and depression [16]. Other recent studies also attribute the effects of hypertension to white matter changes associated with NPS. Although both hypertension and diabetes mellitus contribute to the development of white matter abnormalities, only white matter change by hypertension was linked to NPS. That is because that the mechanisms and consequences are different. White matter abnormalities of hypertension compromised cerebral perfusion, while diabetes attenuated oligodendroglial cell function and lead to demyelinated change [32]. So, it is possible that NPS are the consequences of functional brain flaws, not structural defects [32]. Several limitations of the present study exist. First, this was a small sized study using a single centre dementia registry, and AD patients at a mild stage. However, the composition and ratio of the NPS was consistent with many other studies. Over 90% of patients reported at least one NPS and this high prevalence of NPS is in line with previous studies. The most frequent symptoms
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Figure 1. Patients included for the present study.
were apathy, irritability and depression, which have been consistently found in other studies [33–37] including a Korean study [38]. The CDR score ranged from 0 to 3, which included the severe dementia patients. Second, although half of the patients suffered from two or more NPS, the statistical analysis was performed oblivious of the overlapping symptoms. Recent studies often classify the NPS as being in four groups including psychosis, af C
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fective disorders, apathy and agitation/aggression [39] or three groups containing an affective syndrome, a psychotic syndrome and other neuropsychiatric disturbances [40]. However, recent study which systemically evaluates NPS coming from factor analyses showed a relatively low concordance of symptom clusters among the studies, possibly due to the heterogeneity of populations [41]. Moreover, “apathy” and “depression”, which
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Table 1.
Summary of demographic characteristics.
Characteristics
N = 162 (SD)
Max
Min
Female gender Mean age (years) Mean years of education MMSE CDR Vascular risk factors Hypertension Diabetes mellitus Cardiovascular events Hyperlipidemia Asymptomatic stroke WMH grade Minimal Moderate Severe E4 allele of the Apoprotein E ε4 carrier ε4 non-carrier
104 (64.2%) 74.06 (6.46) 6.93 (5.38) 18.85 (5.13) 0.68 (0.44)
89.0 24.0 27.0 3.0
56.0 0 3.0 0.5
96 (59.3%) 33 (20.4%) 22 (13.6%) 25 (15.4%) 14 (8.6%)
are key NPS in the present study, are classified as different subsyndrome cluster in the most studies. Third, locations of AS were not evaluated. It might be important to characterise different locations of AS. Further studies considering subdivisions into microangiopathic white matter lesions or cortical ischaemias could be helpful. Finally, this was a retrospective, cross-sectional and observational study. Further longitudinal studies whether prevention of AS could attenuate the NPS are needed.
Conclusion In summary, our result suggests that the presence of hypertension and AS increases the severity of apathy and depression in AD. Clinicians of patients who have hypertension and AS in AD would be better to expect the more severe NPS including apathy and depression, and prepare for that.
101 (62.3%) 53 (32.7%) 8 (4.9%) N = 127 (78.4%) 76 (59.8%) 51 (40.2%)
MMSE, The mini mental state examination.
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Table 2.
Severity and frequency of neuropsychiatric symptoms. Patients with symptoms
Neuropsychiatric symptoms Apathy Depression Irritability Anxiety Eating abnormalities Agitation Night-time behavioor disturbance Aberrant motor behaviour Delusion Disinhibition Euphoria/Elation Hallucinations
Mean (SD)
N
%
Min-Max
2.72 (3.09) 1.06 (1.81) 1.46 (2.25) 1.28 (2.17) 1.48 (2.46) 0.97 (1.80) 1.21 (2.38)
109 75 79 64 64 56 47
67.3 46.3 48.8 39.5 39.5 34.6 29.0
0–12 0–12 0–12 0–9 0–12 0–9 0–12
1.05 (2.39)
36
22.2
0–12
0.73 (1.93) 0.70 (2.04) 0.15 (0.83) 0.14 (0.97)
35 34 11 11
21.6 21.0 6.8 6.8
0–12 0–12 0–8 0–12
Table 3. Vascular risk factors related with the severity of neuropsychiatric symptoms controlled by covariates. NPS
Vascular risk factors
Apathy
Without hypertension With hypertension Depression Without AS With AS
NPS, Neuropsychiatric symptoms.
Mean (SD)
R
1.916 (0.380) 0.231 3.169 (0.277) 0.933 (0.163) 0.255 3.329 (0.535)
p value 0.015 0.007
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RESEARCH ARTICLE
Vascular factors are associated with the severity of the neuropsychiatric symptoms in Alzheimer’s disease Yeonsil Moon,1 Heejin Kim,1 Jin Ok Kim,1 and Seol-Heui Han1,2 1
Department of Neurology, Konkuk University Medical Center, Seoul, Republic of Korea; 2 Center for Geriatric Neuroscience Research, Institute of Biomedical Science, Konkuk Medical Science Research Center, Konkuk University, Seoul, Republic of Korea Introduction: The purpose of this study is to determine whether vascular risk factors are associated with severity of neuropsychiatric symptoms (NPS) in patients of Alzheimer’s dementia. Methods: We reviewed medical records of 162 patients with Alzheimer’s dementia. The NPS were assessed using the Neuropsychiatric Inventory (NPI). Hypertension and cardiovascular events were detected through detailed history taking. Diabetes mellitus and hyperlipidemia were uncovered through laboratory test. The asymptomatic stroke and white matter hyperintensities (WMH) were defined by magnetic resonance imaging. Partial correlation analysis was used. Results: Hypertension was correlated with the severity of apathy (r = 0.231, p = 0.015). The asymptomatic stroke was related to the severity of depression (r = 0.255, p = 0.007). The remaining vascular factors were not significant. Conclusion: Presence of hypertension and asymptomatic stroke are related with the severity of apathy and depression in Alzheimer’s dementia. KEYWORDS: hypertension, asymptomatic stroke, apathy, depression
Introduction Dementia is a syndrome with cognitive decline and behaviour problems that lead to impairments in activities of daily living (ADL). Although cognitive impairment is the most important problem that compromises ADL, neuropsychiatric symptoms (NPS) also have practical effects on the quality of life [1–3]. The NPS are risk factors which lead the Alzheimer’s disease (AD) patients to impairment in instrumental ADL more rapidly, and increase the mortality of AD patients [4,5]. The NPS are poorly correlated with cognitive decline and respond to medication unsatisfactorily. While cognitive decline is associated with atrophy of hippocampus and posterior association cortex [6], NPS are associated with diverse structures except hippocampus [7–9]. This dissociation suggests that risk factors contributing to NPS might be different from those of cognitive decline.
Received 18 July 2013; revised 14 October 2013; accepted 14 October 2013 Correspondence: Seol-Heui Han, Department of Neurology, 143–729, Konkuk University Medical Center, 120–1 Neungdong-ro (Hwayang-dong), Gwangjin-gu, Seoul, Republic of Korea. Tel: +82–2–2030–7460. Fax: +82–2–2030–7469 E-mail: [email protected]
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Many risk factors contributing to NPS has been revealed. Depression, apathy, agitation, aggression and psychosis, are confirmed as significant consequences of aging [10–12]. Less education is associated with increased rates of depression, agitation and aggression [13]. The E4 allele of the Apolipoprotein E (ApoE) is one of the noted risk factors for NPS in AD patients. Some studies report that agitation, aggression, depression and psychosis (such as delusions and hallucinations) are more common in patients with the ApoE e4 allele [14,15]. Vascular factors also contribute to the development of NPS. Stroke prior to the onset of AD and hypertension increase the risk of delusion, depression, apathy, anxiety and aggression [16]. The white mater hyperintensities (WMH) in patients with dementia are associated with a dysexecutive-related behavioural symptom in AD [17]. These vascular risk factors that increase NPS are critical because they are modifiable. However, little is known about the relationship between vascular risk factors and the NPS of AD, especially with severity of symptoms. The aim of this study is to determine whether vascular risk factors – including hypertension, diabetes mellitus, hyperlipidemia, cardiovascular events, WMH and asymptomatic stroke (AS) – are associated with severity of NPS in AD.
Vascular factors and neuropsychiatric symptoms
Methods Subjects We retrospectively reviewed medical records of patients with dementia from the Konkuk dementia registry. The Konkuk dementia registry is pooled data from patients who visited the memory clinic for cognitive and behavioural disturbances between March 2006 and October 2010. The data includes all available information such as basic demographic characteristics, other medical conditions, results of laboratory tests, global cognitive assessment, ApoE genotyping and brain imaging. Basic demographic characteristics include age, sex and years of education. Laboratory tests include complete blood count, electrolytes, total, High-density lipoprotein (HDL) and Low-density lipoprotein (LDL) cholesterol, triglyceride, free T4, T3, Thyroid-stimulating hormone, Human Immunodeficiency Virus, Venereal Disease Research Laboratory (VDRL), vitamin B12, folate and homocysteine levels. Comprehensive neuropsychological assessments were also included, which consisted of the modified Korean version of the Hopkins Verbal Learning Test for verbal memory, the Digit Span Forward and Backward for attention and working memory, the Rey-Osterrieth Complex Figure Test for nonverbal, visuospatial memory, the Korean version of the Boston Naming Test for language, the Stroop Test and the Word Fluency Test for frontal lobe function and the Rey-Osterrieth Complex Figure copy test for visuospatial function. ApoE genotyping was done after consent of the patients or carers, and brain imaging was acquired using brain magnetic resonance image (MRI). All data were collected during the second visit, which was within 1 to 2 months of the first visit. All the patients provided written informed consent to use their clinical data for research purposes, and this study was approved by the Institutional Review Boards of the Konkuk University Hospital.
Assessment of dementia Clinical diagnosis of dementia was assigned after review of all accessible information at consensus conferences that were attended by experienced neurologists and neuropsychologists. The diagnosis of AD followed National Institute of Neurological and Communicative Disorders and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria [18]. Only patients with a clinical diagnosis of ‘Probable AD’ were selected for the study. Patients with other dementia, or with mixed or atypical AD were excluded. AS which is not responsible for cognitive decline was not excluded from AD according to the criteria of the NINCDS-ADRDA. C
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Assessment of neuropsychiatric symptoms The NPS were assessed using the Neuropsychiatric Inventory (NPI). The NPI is a retrospective structured informant based rating scale used for patients with dementia [19]. The carer of the dementia patient scores each of 12 NPS; delusions, hallucinations, agitation, depression, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behaviour, night-time behaviour disturbances and appetite and eating abnormalities. The severity and frequency of each symptom are rated, and the descriptive score is obtained by multiplying severity by frequency. As the NPS were assessed at the second visit and the patients who are taking psychiatric drugs were not included in the registry, we could suppose that the concomitant pharmacological effect was excluded.
Definition of vascular risk factors and covariate Hypertension and diabetes mellitus were based on selfreport and medical record. Cardiovascular conditions that preceded the onset of dementia were ascertained through direct questions for heart attack, coronary artery bypass graft or stent insertion. Hyperlipidemia was diagnosed using the cut-off points of serum total cholesterol, HDL and LDL estimated through the laboratory test [20]. The AS was defined by MRI. MR images were obtained at the Konkuk University Medical Center using 3.0 Tesla unit (Signa HDx; GE Healthcare, Milwaukee, Wis) with an 8-channel high-resolution head coil. The axial and sagittal T1-weighted inversion-recovery [TR/TE/TI, 2468/12/920 ms; section thickness, 5 mm; matrix, 512 × 224); 2] axial T2-weighted fast spinecho (TR/effective TE, 4000/106 ms; section thickness, 5 mm; matrix 384 × 384); 3), axial fluid-attenuated inversion-recovery (TR/TE/TI, 11,000/105/2600 ms; section thickness, 5 mm; matrix, 384 × 224); 4) images of MRI was used for this study. The AS was defined as a focal hyperintense lesion on T2-weighted axial images and FLAIR of the patient who do not have corresponding symptoms in past history. The modified criteria of Fazekas et al. [21] or Scheltens et al. [22] was applied for evaluating the severity of WMH semiquantitatively, which is proposed by the Clinical Research for Dementia Of South Korea (CREDOS). The way to apply the scale is described in elsewhere, and the scale is confirmed through the high inter-rater and intra-rater reliabilities [23]. Dementia severity was interpreted using a global Clinical Dementia Rating (CDR) Score, which ranged from 0 to 3 [24].
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Statistical analysis Statistical analysis was done with SPSS version 17.0. Partial correlation analysis was used to predict the relationship of the NPS and the vascular risk factors. Age, educational level, presence of the ApoE e4 allele, severity of dementia (CDR score) and the other NPS except the target NPS were selected as covariates. These covariates are factors suggested to have effects on NPS based on previous reports. The p values of less than 0.05 were considered to indicate statistically significant differences.
Results Of the 579 data from the Konkuk dementia registry, 173 patients were diagnosed as “Probable AD”. Eleven patients were excluded because of incomplete data of the 173. Finally, data of the remaining 162 patients with probable AD were used for this study. (Figure 1) The general baseline characteristics of the patients for this study are detailed in Table 1. Female subjects were dominant, and the mean age was 74.06. The mean number of years of education was relatively low, 6.93 years. The range of CDR scores was 0.0 to 3.0, and most of the patients were in the very mild stage (CDR 0.5, 61.1%; CDR 1, 26.5%). More than half of the patients reported hypertension (59.3%), and 20.4% presented with diabetes mellitus. Cardiovascular events and hyperlipidemia were less common (13.6%, 15.4%). 8.6% of the patients had AS, and 62.3% of the patients revealed minimal WMH. About 60% of the patients had the ApoE e4 allele. Almost all patients reported at least one NPS (92%), and the severity of the NPS was relatively moderate (range of the total NPI was 0 to 75, Table 2). Apathy was the most common NPS (67.3%), and irritability and depression were also prevalent (48.8% and 46.3%, respectively). Elation and hallucination were the most uncommon symptoms, each presenting in 11 patients (6.8%). Age, educational level, presence of the ApoE e4 allele, and severity of dementia and WMH were correlated with scores of NPI. After adjusting for these factors, some vascular factors were associated with scores of NPI. Hypertension was correlated with the severity of apathy (r = 0.231, p = 0.015). The AS were related to the severity of depression (r = 0.255, p = 0.007) (Table 3). The remaining vascular factors (diabetes mellitus, hyperlipidemia, cardiovascular events and WMH) were not significant.
Discussion Hypertension breaks the blood–brain barrier and weakens the cerebral microcirculation. The impaired autoregulation leads the hemodynamic reserve to be reduced, which is a common cause of the decreased cerebral perfusion [25]. Hypoperfusion and the abnormal lesions that involve the posterior limb of the internal capsule [26], subcortical areas [27] and bilateral basal ganglia [28] are associated with apathy. These lesions are all on the path of the frontal-subcortical system from basal ganglia to frontal cortex, and damage of the frontalsubcortical system results in dopaminergic dysfunction. In AD, dopamine transporter uptake in the putamen is correlated with apathy [29]. The AS was the strongest factor that aggravated the depression. Lacunar infarctions or microbleeds in thalamus, basal ganglia and deep white matter are significantly associated with poststroke depression. Even though we did not systemically classify the locations of AS, almost all AS were lacunar infarctions in bilateral basal ganglia and thalamus which show no identifiable symptom. Disruption of the chemical neuroanatomy related to the frontal/temporal lobe-basal ganglia-ventral brainstem circuitry could result in dysfunction of the serotonergic systems, which are crucial components of mood [30,31]. In the present study, other vascular factors (diabetes mellitus, cardiovascular events) were not significantly associated with any NPS. This is similar with previous results which showed that diabetes mellitus, hyperlipidemia and cardiovascular events are not associated with the prevalence of any NPS; otherwise, hypertension and stroke were linked to agitation, anxiety, delusion, apathy and depression [16]. Other recent studies also attribute the effects of hypertension to white matter changes associated with NPS. Although both hypertension and diabetes mellitus contribute to the development of white matter abnormalities, only white matter change by hypertension was linked to NPS. That is because that the mechanisms and consequences are different. White matter abnormalities of hypertension compromised cerebral perfusion, while diabetes attenuated oligodendroglial cell function and lead to demyelinated change [32]. So, it is possible that NPS are the consequences of functional brain flaws, not structural defects [32]. Several limitations of the present study exist. First, this was a small sized study using a single centre dementia registry, and AD patients at a mild stage. However, the composition and ratio of the NPS was consistent with many other studies. Over 90% of patients reported at least one NPS and this high prevalence of NPS is in line with previous studies. The most frequent symptoms
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Figure 1. Patients included for the present study.
were apathy, irritability and depression, which have been consistently found in other studies [33–37] including a Korean study [38]. The CDR score ranged from 0 to 3, which included the severe dementia patients. Second, although half of the patients suffered from two or more NPS, the statistical analysis was performed oblivious of the overlapping symptoms. Recent studies often classify the NPS as being in four groups including psychosis, af C
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fective disorders, apathy and agitation/aggression [39] or three groups containing an affective syndrome, a psychotic syndrome and other neuropsychiatric disturbances [40]. However, recent study which systemically evaluates NPS coming from factor analyses showed a relatively low concordance of symptom clusters among the studies, possibly due to the heterogeneity of populations [41]. Moreover, “apathy” and “depression”, which
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Table 1.
Summary of demographic characteristics.
Characteristics
N = 162 (SD)
Max
Min
Female gender Mean age (years) Mean years of education MMSE CDR Vascular risk factors Hypertension Diabetes mellitus Cardiovascular events Hyperlipidemia Asymptomatic stroke WMH grade Minimal Moderate Severe E4 allele of the Apoprotein E ε4 carrier ε4 non-carrier
104 (64.2%) 74.06 (6.46) 6.93 (5.38) 18.85 (5.13) 0.68 (0.44)
89.0 24.0 27.0 3.0
56.0 0 3.0 0.5
96 (59.3%) 33 (20.4%) 22 (13.6%) 25 (15.4%) 14 (8.6%)
are key NPS in the present study, are classified as different subsyndrome cluster in the most studies. Third, locations of AS were not evaluated. It might be important to characterise different locations of AS. Further studies considering subdivisions into microangiopathic white matter lesions or cortical ischaemias could be helpful. Finally, this was a retrospective, cross-sectional and observational study. Further longitudinal studies whether prevention of AS could attenuate the NPS are needed.
Conclusion In summary, our result suggests that the presence of hypertension and AS increases the severity of apathy and depression in AD. Clinicians of patients who have hypertension and AS in AD would be better to expect the more severe NPS including apathy and depression, and prepare for that.
101 (62.3%) 53 (32.7%) 8 (4.9%) N = 127 (78.4%) 76 (59.8%) 51 (40.2%)
MMSE, The mini mental state examination.
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Table 2.
Severity and frequency of neuropsychiatric symptoms. Patients with symptoms
Neuropsychiatric symptoms Apathy Depression Irritability Anxiety Eating abnormalities Agitation Night-time behavioor disturbance Aberrant motor behaviour Delusion Disinhibition Euphoria/Elation Hallucinations
Mean (SD)
N
%
Min-Max
2.72 (3.09) 1.06 (1.81) 1.46 (2.25) 1.28 (2.17) 1.48 (2.46) 0.97 (1.80) 1.21 (2.38)
109 75 79 64 64 56 47
67.3 46.3 48.8 39.5 39.5 34.6 29.0
0–12 0–12 0–12 0–9 0–12 0–9 0–12
1.05 (2.39)
36
22.2
0–12
0.73 (1.93) 0.70 (2.04) 0.15 (0.83) 0.14 (0.97)
35 34 11 11
21.6 21.0 6.8 6.8
0–12 0–12 0–8 0–12
Table 3. Vascular risk factors related with the severity of neuropsychiatric symptoms controlled by covariates. NPS
Vascular risk factors
Apathy
Without hypertension With hypertension Depression Without AS With AS
NPS, Neuropsychiatric symptoms.
Mean (SD)
R
1.916 (0.380) 0.231 3.169 (0.277) 0.933 (0.163) 0.255 3.329 (0.535)
p value 0.015 0.007
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